Caspase Control: Protagonists of Cancer Cell Apoptosis

Caspase Control: Protagonists of Cancer Cell Apoptosis

Emergence of castration-resistant metastatic prostate cancer is due to activation of survival pathways, including apoptosis suppression and anoikis resistance, and increased neovascularization. Thus targeting of apoptotic players is of critical significance in prostate cancer therapy since loss of a...

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Дата:2012
Автори: Fiandalo, M.V., Kyprianou, N.
Формат: Стаття
Мова:English
Опубліковано: Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України 2012
Назва видання:Experimental Oncology
Теми:
Reviews
Онлайн доступ:http://dspace.nbuv.gov.ua/handle/123456789/139061
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Назва журналу:Digital Library of Periodicals of National Academy of Sciences of Ukraine
Цитувати:Caspase Control: Protagonists of Cancer Cell Apoptosis / M.V. Fiandalo, N. Kyprianou // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 165-175. — Бібліогр.: 150 назв. — англ.

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Digital Library of Periodicals of National Academy of Sciences of Ukraine
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spelling irk-123456789-1390612018-06-20T03:11:52Z Caspase Control: Protagonists of Cancer Cell Apoptosis Fiandalo, M.V. Kyprianou, N. Reviews Emergence of castration-resistant metastatic prostate cancer is due to activation of survival pathways, including apoptosis suppression and anoikis resistance, and increased neovascularization. Thus targeting of apoptotic players is of critical significance in prostate cancer therapy since loss of apoptosis and resistance to anoikis are critical in aberrant malignant growth, metastasis and conferring therapeutic failure. The majority of therapeutic agents act through intrinsic mitochondrial, extrinsic death receptor pathways or endoplasmic reticulum stress pathways to induce apoptosis. Current therapeutic strategies target restoring regulatory molecules that govern the pro-survival pathways such as PTEN which regulates AKT activity. Other strategies focus on reactivating the apoptotic pathways either by down-regulating anti-apoptotic players such as BCL-2 or by up-regulating pro-apoptotic protein families, most notably, the caspases. Caspases are a family of cystine proteases which serve critical roles in apoptotic and inflammatory signaling pathways. During tumorigenesis, significant loss or inactivation of lead members in the caspase family leads to impairing apoptosis induction, causing a dramatic imbalance in the growth dynamics, ultimately resulting in aberrant growth of human cancers. Recent exploitation of apoptosis pathways towards re-instating apoptosis induction via caspase re-activation has provided new molecular platforms for the development of therapeutic strategies effective against advanced prostate cancer as well as other solid tumors. This review will discuss the current cellular landscape featuring the caspase family in tumor cells and their activation via pharmacologic intervention towards optimized anti-cancer therapeutic modalities. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”. 2012 Article Caspase Control: Protagonists of Cancer Cell Apoptosis / M.V. Fiandalo, N. Kyprianou // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 165-175. — Бібліогр.: 150 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/139061 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
institution Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection DSpace DC
language English
topic Reviews
Reviews
spellingShingle Reviews
Reviews
Fiandalo, M.V.
Kyprianou, N.
Caspase Control: Protagonists of Cancer Cell Apoptosis
Experimental Oncology
description Emergence of castration-resistant metastatic prostate cancer is due to activation of survival pathways, including apoptosis suppression and anoikis resistance, and increased neovascularization. Thus targeting of apoptotic players is of critical significance in prostate cancer therapy since loss of apoptosis and resistance to anoikis are critical in aberrant malignant growth, metastasis and conferring therapeutic failure. The majority of therapeutic agents act through intrinsic mitochondrial, extrinsic death receptor pathways or endoplasmic reticulum stress pathways to induce apoptosis. Current therapeutic strategies target restoring regulatory molecules that govern the pro-survival pathways such as PTEN which regulates AKT activity. Other strategies focus on reactivating the apoptotic pathways either by down-regulating anti-apoptotic players such as BCL-2 or by up-regulating pro-apoptotic protein families, most notably, the caspases. Caspases are a family of cystine proteases which serve critical roles in apoptotic and inflammatory signaling pathways. During tumorigenesis, significant loss or inactivation of lead members in the caspase family leads to impairing apoptosis induction, causing a dramatic imbalance in the growth dynamics, ultimately resulting in aberrant growth of human cancers. Recent exploitation of apoptosis pathways towards re-instating apoptosis induction via caspase re-activation has provided new molecular platforms for the development of therapeutic strategies effective against advanced prostate cancer as well as other solid tumors. This review will discuss the current cellular landscape featuring the caspase family in tumor cells and their activation via pharmacologic intervention towards optimized anti-cancer therapeutic modalities. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”.
format Article
author Fiandalo, M.V.
Kyprianou, N.
author_facet Fiandalo, M.V.
Kyprianou, N.
author_sort Fiandalo, M.V.
title Caspase Control: Protagonists of Cancer Cell Apoptosis
title_short Caspase Control: Protagonists of Cancer Cell Apoptosis
title_full Caspase Control: Protagonists of Cancer Cell Apoptosis
title_fullStr Caspase Control: Protagonists of Cancer Cell Apoptosis
title_full_unstemmed Caspase Control: Protagonists of Cancer Cell Apoptosis
title_sort caspase control: protagonists of cancer cell apoptosis
publisher Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
publishDate 2012
topic_facet Reviews
url http://dspace.nbuv.gov.ua/handle/123456789/139061
citation_txt Caspase Control: Protagonists of Cancer Cell Apoptosis / M.V. Fiandalo, N. Kyprianou // Experimental Oncology. — 2012. — Т. 34, № 3. — С. 165-175. — Бібліогр.: 150 назв. — англ.
series Experimental Oncology
work_keys_str_mv AT fiandalomv caspasecontrolprotagonistsofcancercellapoptosis
AT kyprianoun caspasecontrolprotagonistsofcancercellapoptosis
first_indexed 2025-07-10T07:32:27Z
last_indexed 2025-07-10T07:32:27Z
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fulltext Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ��� CASPASE CONTROL: PROTAGONISTS OF CANCER CELL APOPTOSIS M.V. Fiandalo, N. Kyprianou* Department of Molecular and Cellular Biochemistry and the Markey Cancer Center, University of Kentucky College of Medicine, Department of Urology, Lexington, KY 40536, USA Emergence of castration-resistant metastatic prostate cancer is due to activation of survival pathways, including apoptosis sup- pression and anoikis resistance, and increased neovascularization. Thus targeting of apoptotic players is of critical significance in prostate cancer therapy since loss of apoptosis and resistance to anoikis are critical in aberrant malignant growth, metastasis and conferring therapeutic failure. The majority of therapeutic agents act through intrinsic mitochondrial, extrinsic death receptor pathways or endoplasmic reticulum stress pathways to induce apoptosis. Current therapeutic strategies target restoring regulatory molecules that govern the pro-survival pathways such as PTEN which regulates AKT activity. Other strategies focus on reactivat- ing the apoptotic pathways either by down-regulating anti-apoptotic players such as BCL-2 or by up-regulating pro-apoptotic protein families, most notably, the caspases. Caspases are a family of cystine proteases which serve critical roles in apoptotic and inflammatory signaling pathways. During tumorigenesis, significant loss or inactivation of lead members in the caspase family leads to impairing apoptosis induction, causing a dramatic imbalance in the growth dynamics, ultimately resulting in aberrant growth of human cancers. Recent exploitation of apoptosis pathways towards re-instating apoptosis induction via caspase re-activation has provided new molecular platforms for the development of therapeutic strategies effective against advanced prostate cancer as well as other solid tumors. This review will discuss the current cellular landscape featuring the caspase family in tumor cells and their activation via pharmacologic intervention towards optimized anti-cancer therapeutic modalities. This article is part of a Spe- cial Issue entitled “Apoptosis: Four Decades Later”. Key Words: apoptosis, caspase-8, proteasome inhibitors. THE CHALLENGE IN CANCER TREATMENT In the year ����� the challenge for clinicians� onco­ lo gists and �asic scientists remains the development of effective therapeutic strategies that �lock malignant cell growth� without impairing normal healthy cells. Investigative efforts focus on successful exploitation of cancer specific characteristics acquired during malignant transformation via a series of genetic and epigenetic mutations resulting in uncontrolled growth and evasion of apoptosis mechanisms [�]. Losing critical regulatory mechanisms that control normal tissue homeostasis ena�les tumor cells to acquire new characteristics such as tissue invasion� metasta­ sis and angiogenesis. �ome of the control pathways are activated such as cell proliferation� cell cycle pro­ gression and pro­survival pathways� while others are down­regulated� like the cell death pathways including apoptosis and anoikis. A�errant cell proliferation during cancer initiation and progression to metastasis is controlled �y cell cycle progression. The cell cycle consists of several phases; G�� G�� �� G�� and Mitosis regulated �y vari­ ous cyclins and CDK �cyclin dependant kinases� and progression from one phase to another is dependent on specific checkpoints [�]. A very critical player at this checkpoint is p�� �notoriously known as the guardian of the genome� due to its role in rescuing damaged DNA� via up­regulation of downstream effectors� such as p�� �induces cell cycle arrest� and PUMA which �locks anti­apoptotic players leading to apoptosis induction [�]. Cell cycle regulation via p�� can prima­ rily �e a�rogated �y loss­of­function mutations� losing p�� activity allows for the cell to replicate regardless of DNA integrity and increases apoptosis resistance [�]. Additional mechanisms of p�� down­regulation involve the over­expression of MDM�� an E� ligase that mediates the polyu�iquitination of p�� resulting in its degradation. Over­expression of MDM� ensures rapid degradation of p�� leading to diminished if not a�olished p�� activity and unregulated cell cycle progression [�]. Proteasome inhi�itors� agents that �lock protein degradation mediated �y ��� protea­ some� have �een shown to sta�ilize p�� and restore p�� mediated apoptosis [�]. Esta�lished chemo­ therapeutic agents such as mitomycin C or doxoru­ �icin are used to induce cell cycle arrest in a variety of epithelial cancers. These agents work to either cross link DNA �mitomycin C� or �ind directly to the DNA intercalating into the dou�le­helix strands caus­ ing the DNA to �ecome rigid and �reak �doxoru�icin� [�]. The major limitation however is that these drugs damage surrounding healthy normal cells� tissues� and organs such as kidney �mitomycin C� or the heart �doxoru�icin� [8� 9]. Treatment of MCF­� �reast cancer xenografts with a com�ination of mitomycin C with Received: July 6, 2012 *Correspondence: E-mail: nkypr2@uky.edu Abbreviations used: APC — allophycocyanin; ATCC — American type culture collection; CRPC — castration-recurrent prostate cancer; DISC — death inducing signaling complex; FADD — Fas associated death domain; GST — glutathione S-transferase; HDAC7 — histone deacetylase 7; IP — immunoprecipitation; MTT — 3-(4,5-dimethylthi- azol-2-yl)-2,5-diphenyltetrazolium bromide; NB7 — neuroblastoma 7; PI — propidium iodide; TNF-α — tumor necrosis factor-α; TRAIL — TNF-alpha related apoptosis inducing ligand. Exp Oncol ���� ��� �� ������� INVITED REVIEW ��� Experimental Oncology ��� �������� ���� ��eptem�er� curcumin significantly decreased mitomycin C related side effects [��]. �trategies involved with overcoming the toxic side effects of doxoru�icin �y changing the mode of doxoru�icin delivery �y encapsulating the drug in titanium nanoparticals which showed promising results [��]. Circumventing the caveats associated with systemic toxicities of these chemotherapeutics involved examining other pro­survival pathways� such as the AKT signaling pathway which can also impact cell cycle regulation and growth arrest. The AKT path­ way is activated through �inding of growth factors to their cognate tyrosine kinase receptors which then carry out the signal transduction through the interplay �etween �RC� phosphatidylinositol­� kinase �PI�K� and phosphotidylinositol­�� �­�isphosphate �PIP��� and phosphotidylinositol­�� �� �­triphosphate �PIP�� and a critical regulatory molecule� PTEN [��]. PTEN� a phosphatase� regulates AKT activation �ecause it dephosphorylates and converts PIP� to PIP� thus preventing PIP��AKT interaction [��]. AKT is a kinase that phosphorylates several different targets such as mTOR� IKK �an inhi�itory �inding protein that pre­ vents the nuclear factor of kappa B �NF­κB� activation�� and cell cycle inhi�itors �p��� p���. In cancer activation of the AKT pathway can �ecome a�errant �ecause of a variety of mutations that can occur within PI3K� AKT� and PTEN [��]. One of the most detrimental and oncogenic potential promoting mutations are those that render these molecules constitutively active. Con­ stitutively active PI�K can lead to the increase in the conversion rate of PIP� to PIP� favoring PIP� produc­ tion leading to increased AKT activation [��]. A spe­ cific AKT mutation� E��K in either AKT� or AKT� leads to constitutive activation and promotes increased trafficking to the plasma mem�rane [��]. PI3K and AKT activating mutations are deleterious for the cell; however� another mechanism that can elevate AKT activity to supra­physiological levels and contri�ute to oncogenesis is the loss of PTEN� a critical regula­ tor of AKT activation. Interrogation of the signaling events dictated �y AKT� mTOR� and PI�K has lead to the development of a powerful class of pharmacologic inhi�itors. The most promising class of AKT inhi�itors are the lipid �ased inhi�itors which essentially inhi�it AKT �inding to the plasma mem�rane. Perifosine has emerged as one of the most promising AKT inhi�itors and has �een through several phase II clinical tri­ als [����9]. The mTOR inhi�itors include rapamycin and its derivatives� such as CCI­��9� �locks mTOR function through similar mechanisms that primarily involve �inding to the co­factor FKBP and together� rapamycin and FBKP �ind to mTOR and inhi�it activity [��]. PI�K inhi�itors like wortmannin or its derivative� LY�9���� �ind covalently to PI�K to inhi�it its kinase activity [��]. These agents however� lack specificity and new carefully designed inhi�itors such as CAL­ ��� �Calistoga� have shown promising results in clini­ cal trials [��] which are on­going at Clearview Cancer institute ������. PI�K inhi�itors exhi�it higher efficacy com�ination with existing chemotherapeutic agents such as� an AKT or mTOR inhi�itors �ecause these com�inations �lock two pathways� eliminating indi­ vidual pathway activity as well as preventing activation of alternate or redundant non­AKT mediated pathways activated through PI�K [��]. PTEN is the direct inhi�i­ tor of AKT �ecause it converts AKT activating PIP� into PIP�� which does not activate AKT. PTEN studies have revealed that PTEN may �e down­regulated either through inactivating mutations� gene deletions� and phosphorylation of PTEN �y CK� have the same result� persistent AKT signaling that contri�utes to tumor formation [��]. PTEN loss has �een associated with several cancers at the advanced stage of disease� including prostate cancer [��]. PTEN mutations have �een linked with aggressive androgen dependant or androgen independent �termed castration recur­ rent� prostate cancer [��� ��] and evidence suggests that oncogenesis results due to the loss of AKT and cell cycle regulation [��� �8]. Prostate cancer is one of the most prevalent causes of cancer related death in males with several risk factors� such as age� race� and diet contri�uting towards prostate cancer development and progression [�9]. Regulation of androgen signaling via the andro­ gen receptor �AR� is critical to maintaining prostate homeostasis. The androgen axis involves conver­ sion of testosterone into �α­dihydrotestosterone �y �α­reductase� the active meta�olite that �inds to AR and the ligand­receptor complex is translocated to the nucleus to activate su�sequent signaling path­ ways [��]. When prostate cells undergo tumorgenesis they take on different molecular characteristics� one of the more prominent changes is the up­regulation of androgen receptor either through gene amplifica­ tion or through other processes leading to AR over­ expression [��]. �uch an event prominently activates AR pathways leading to increased proliferation and reduced apoptosis� or may further sensitize prostate cancer cells to growth factors stimuli such as EGFR [��]. Currently the most promising therapy for treating castration­recurrent prostate cancer �CRPC�� involves chemically depleting androgens in the prostate �y in­ hi�itors of androgen axis such as a�iraterone [��]. Additional agents are currently �eing tested in clinical trials such as MDV���� which is a competitive inhi�i­ tor �locking AR�androgen signaling with therapeutic promise in prostate cancer patients [��]. Another class of chemotherapeutics are protea­ some inhi�itors capa�le of inducing apoptosis and thus with great potential as anti­cancer agents [��]. There are two types of proteasome inhi�itors� natural inhi�i­ tors �lactacystin and epoxomicin� and synthetic inhi�i­ tors such as MG��� and velcade [��]. MG��� inhi�its the chymotrypsin like activity of the ��� proteasome [��]. Velcade� �P�­���/�ortizomi�� is an FDA ap­ proved proteasome inhi�itor used in treating multiple myeloma [�8]. Velcade is a dipeptide �oronic acid small molecule that �locks the chymotrypsin­like activity of the ��� particle [�9]. Investigators have Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ��� reported that velcade has an impact on several key cellular processes such as inhi�iting cell cycle and NF­κB activation [��]. Velcade sensitizes cancer cells to apoptosis through several mechanisms� such as the down­regulation of c­FLIP� which inhi�its cas­ pase­8 activation at the DI�C [��]. �everal in vitro and in vivo studies have shown that velcade induces apoptosis in multiple myeloma cells [��]. However multiple myeloma patients are either initially resistant or acquired resistance to velcade during the course of treatment [��]. Attempts to overcome velcade resistance have led to development of various com­ �inations of velcade with different chemotherapeutic agents such as� PCI­���8� �an HDAC inhi�itor� which was found to synergize with velcade to induce reactive oxygen species damage as well as caspase­8 activa­ tion in non­Hodgkins lymphoma [��]. �ignificantly enough� Mitsiades and colleagues [��]� showed that velcade in com�ination with doxoru�icin can overcome velcade resistance in multiple myeloma. Another anti­ cancer strategy involved using velcade in com�ination with TNF­α related apoptosis inducing ligand �TRAIL�. Recent studies �y Christian et al. suggests the a�ility of velcade to sensitize TRAIL­resistant prostate can­ cer cell lines in vitro and in vivo to TRAIL­mediated apoptosis and together TRAIL and velcade sta�ilize caspase­8 p�8 su�unit [��� ��]. A major caveat for using velcade as an anti­cancer strategy is the lack of cell type and cell signaling specificity. Velcade was designed to �lock the protea­ some and not to discriminate �etween a malignant or a healthy cell therefore� all cells are impacted �y vel­ cade treatment. Velcade treatment can lead to side effects such as throm�ocytopenia and peripheral neuropathy [�8]. To �ypass the caveats associated with velcade� while achieving apoptosis induction investigators are pursuing the activity of E� ligases in an attempt to achieve and their involvement with the extrinsic pathway of apoptosis. For CRPC� taxanes provide the only clinically ef­ fective chemotherapeutic approach. These agents target microtu�ules and the cellular cytoskeleton� thus sta�ilizing microtu�ules and preventing microtu�ule reorganization� towards disruption of kinetochore formation during mitosis [�9]. Proposed mechanisms conferring taxane resistance involve either microtu�ule mutations that prevent drug �inding or the cell itself pumps out the taxane through P­glycoprotein pumps [��]. Taxanes have �een used against other solid tumors such as �reast� lung� ovarian� and esopha­ geal cancers [��� ��]. Alternative approaches involve inducing or restoring the apoptotic pathways through a variety of other agents such as staurosporin� etopo­ side� and a new emerging class of apoptosis inducing agents� the death ligands such as TRAIL. MECHANISMS OF APOPTOSIS REGULATION Apoptosis �programmed cell death� plays a critical role in regulating cell growth and tissue development. �ince loss of apoptosis leads to tumor initiation� growth� and progression [��]� exploitation of apoptosis mechanisms can lead to developing new anticancer strategies� that can effectively impair the tumorigenic process. Each pathway of apoptosis is activated �y dif­ ferent triggers such as cell­detachment �anoikis� mito­ chondrial signals �intrinsic pathway�� or death ligands �extrinsic pathway� �Figs. � and ��. Cellular insult ECM Cytosol AKT BAX BADBCL2 MOMP opening Caspase-2 Caspase-9 Caspase-4 Caspase 3, 7 Caspase-12 Endoplasmic reticulum tBID XIAP SMAC Diablo Apoptosome Processed caspase-9 Apoptosis APAF-1 Cleaves downstream targets Cytochrome C release Mitochondria Fig. 1. Intrinsic and ER pathways of apoptosis. The intrin­ sic pathway of apoptosis activated �y various stimuli� leads to a down­regulation of anti­apoptotic BCL­� family mem�ers� allowing pro­apoptotic mem�ers to pertur� the mitochondria. Cytochrome c release from the mitochondria leads to APAF­� and pro­caspase­9 recruitment forming the apoptosome; cas­ pase­9 is then activated� cleaving downstream targets� such as executioner caspase­� and ­�. The ER stress pathway induces the activation of caspase­� or ­�� leading to caspase­�� activa­ tion� which then activates the intrinsic pathway of apoptosis Cleaves downstream targets Caspase 3, 7 Apoptosis ECM Cytosol TRAIL TRAIL Receptor c-Flip FADD Initiator Pro-caspase-8 Processed caspase-8 processed HDAC7 BID Intrinsic Pathway activated Death Inducing Signaling Complex (DISC)p43/41 Pro Pro 18 18 18 18 10 10 10 10 Fig. 2. TRAIL­mediated extrinsic pathway of apoptosis. Medi­ ated through the �inding of TRAIL to its cognate receptor� upon �inding the receptors oligomerize within the mem�rane. Fas associated death domain �FADD� is recruited� followed �y pro­ caspase­8 which is then processed into its active p�8 and p�� su�units which then can oligomerize into a heterotetramer A mechanism designed to protect against cellular metastasis is anoikis� which is an apoptosis pro­ gram that is induced upon the loss of critical protein interactions �etween the cell and the extracellular matrix. The major players and pathways involved with anoikis are integrin� focal adhesion� and growth fac­ tors �IGF­�� interactions as well as the JNK pathway� and caspase activation signaling events [��]. Anoikis plays a role in all tissue development and regenera­ tion and in preventing epithelial cell detachment and migration in normal and tumor cells [��]� including ��8 Experimental Oncology ��� �������� ���� ��eptem�er� shedding of colon epithelial cells [��] and mammary gland reduction [��� �8]. Anoikis is initiated when adherent cells detach from the �asement mem�rane� more specifically� the loss of integrin �either α� or β�� signaling with the focal adhesion points [�9]. Apoptotic pathways are activated upon cell detachment and loss of integrin signaling in normal cells; cancer cells develop resistance to anoikis through diverse mecha­ nisms such as over­coming the loss of focal adhesion kinase �FAK�� overexpression of talin �integrin partner/ focal adhesion player�� acquiring mutations in FAK that trigger anoikis inhi�itory mechanisms or navigat­ ing stimuli from the microenvironment signaling loss of apoptotic pathways [��]. The intrinsic pathway of apoptosis is under heavy regulation �y several different types of mo­ lecules that can �e separated into two main classes� anti­apoptotic proteins such as the XIAP �inhi�itors of apoptosis�� BCL­� family proteins such as BCL­�� BCL­xL or the pro­apoptotic proteins� which include BCL­� family mem�ers; BAX� BAD� BID� �MAC� and Dia�lo are activated through signaling events that lead to mitochondrial outer mem�rane permea�iliza­ tion �MOMP�. Cytochrome c is released� �inds with APAF­� and caspase­9 to form the apoptosome [��]. Upon apoptosome formation� caspase­9 �ecomes catalytically active and acts on downstream targets including caspase­� and ­� �Fig. �� [��]. Tumor cells can inactivate apoptotic signaling programs �y engag­ ing anti­apoptotic mechanisms involving the up­regu­ lation of apoptotic suppressors �Bcl­�� Bcl­xL� and/ or through the down­regulation of critical apoptosis in­ ducing players such as the caspase family �caspase­�� ­�� ­�� ­8� ­9� ­��� ­��� [��]. Mechanisms that inhi�it the intrinsic pathway of apoptosis are interconnected with activities of the AKT �Fig. �� and NF­κB pathways. Therefore� activated AKT pathway inhi�its the intrin­ sic pathway of apoptosis as AKT signaling promotes BCL­� and BCL­xL activity while inhi�iting BAX and BAD players involved with inducing apoptosis [��]. Blocking BAX and BAD activity can prevent MOMP from opening� thus preventing cytochrome c release� and consequentially inhi�iting apoptosome forma­ tion. Another family of anti­apoptotic proteins that can inhi�it �oth the intrinsic and extrinsic pathways is the inhi�itors of apoptosis �IAP� which have two arms� the cIAP or X­linked IAP �XIAP�. The IAP family consists of E� ligases that can �lock apoptosome formation through �inding directly to APAF­� or caspase­9� thus inhi�iting caspase­9 activation [��]. XIAP also �ind directly to caspase­� preventing its activation� and in­addition to �locking activation XIAP can facilitate the transfer of u�iquitin� there�y tagging the caspases for degradation �y the ��� proteasome [��]. There are also mutations acquired in the pro­apoptotic ma­ chinery itself� the most nota�le mutations �eing those occurring in the caspase family. To that end� �rinvisula et al.� identified caspase­9β� a caspase­9 mutant that lacks the large active su�unit and esta�lished that caspase­9β acts in a dominant negative fashion pre­ venting caspase­� activation [��]. Moreover� Park and colleagues identified several gene polymorphisms that give rise to altered forms of caspase­9 that impair caspase­9 activity and there�y �lock apop­ tosis induction [�8]. Post­translational modification of caspase­9 phosphorylation at Thr ��9 mediated as a result of CDK­� and cyclin B in cell cycle [�9] also prevents caspase­9 recruitment to the apoptosome �locking caspase­9 activation. Regardless of how caspase­9 is modified� if this caspase fails to �e­ come active then the su�sequently executioner cas­ pase­�/­� activation is inhi�ited� ultimately impairing the intrinsic pathway of apoptosis activation [��� ��]. The extrinsic pathway �also referred to as the death receptor pathway� involves the induction of apoptosis through the activation of death receptors via death ligands such as tumor necrosis factor­α �TNF­α�� FA�L� and TRAIL [��]. While FA�L and TRAIL strictly activate the extrinsic pathway mediated apoptosis� TNF­α can play two different roles� although this mole­ cule is capa�le of inducing apoptosis� TNF­α is also capa�le of activating pro­survival pathway. TNF­acti­ vation impacts several critical cellular pathways some of which include cellular proliferation� differentiation� and apoptosis [��]. �pecifically� TNF­α �inding to its cognate receptor can lead to the formation of two separate complexes� complex � which can lead to the induction of either the NF­κB pathway �pro­survival� [��] or complex � which activates the apoptotic pathway mediated primarily through Fas associated death domain �FADD� and caspase­8 activation [��]. Complex � mediated NF­κB induction is initiated through the �inding of TNF­α to its cognate receptor TNFR­� which then leads to the recruitment of two adaptor proteins TNF receptor­associated protein with a death domain �TRADD� and receptor­interacting protein � �RIP�� [��]. Upon �inding of TRADD another adaptor molecule� TNF associated factor­� �TRAF�� followed �y the recruitment of cIAP �cellular inhi�itors of apoptosis�� as well as U�c� and U�c�� �E� u�iq­ uitin conjugating enzymes� [��] to form complex �. Once complex � is formed� TRAF� is phosphorylated �y PKC resulting in K�� link polyu�iquitination [�8] that leads to proteasomal degradation [�9]. TRAF�� cIAP� and U�c�� function in concert to facilitate K�� linked polyu�iquitination of RIP� [8�]. K�� linked polyu�iquitination of RIP­� leads to activation of Tak�/ TAB complex to activate the IKK complex [8�]. The IKK complex consists of several components� IKK α� IKK β� and IKK γ� this kinase complex phosphorylates the inhi�itor of kappa B molecule �IκB­α� [8�]. IκB α� is a �ound inhi�itor of NF­κB that functions to prevent nuclear import of NF­κB into the nucleus. Nuclear translocation of NF­κB results in �inding to its re­ spective DNA �inding sites and gene activation [8�]. NF­κB up­regulates several different gene types� such as inflammatory response pro­survival genes� BCL­� family� caspase­8 inhi�itor c­FLIP� cIAP and angiogenesis players and proliferation genes� cyclin D� and MYC [8�]. Interestingly enough� proteasome Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ��9 inhi�ition can impede the NF­κB pathway as it prevents proteasome degradation of IκB­α thus leading to de­ creased activation of NF­κB [8�]. Apoptosis induction through complex � of the TNF­α pathway proceeds via depletion of c­FLIP and/ or c­IAP expression� as well RIP� kinase phosphoryla­ tion [8�� 8�]. Once phosphorylated� RIP�� FADD and initiator caspase­8 are recruited thus assem�ling com­ plex �. Once complex � is formed� caspase­8 is pro­ cessed and can then cleave its downstream targets� caspase­� and ­�� towards apoptosis execution [88]. Recent evidence identified the ripoptosome� a �mD apoptosis signaling complex composed of RIP­�� FADD� and caspase­8m as a key player in apoptosis activation [89]. This complex assem�les when cIAP expression levels are depleted� either through up­reg­ ulation of �MAC� a direct inhi�itor of cIAP� or through �MAC mimetics or other chemotherapeutics such as etoposide� which is a topoisomerase II inhi�itor used to treat solid tumors. In addition to inducing DNA �reaks� etoposide can down­regulate cIAPs [89�9�]. The a�ility to form this apoptosis inducing complex� can serve as a powerful tool for developing anti­ cancer strategies �ecause an agent �or com�ination of agents� could induce apoptosis� while �ypassing the normal requirements for apoptosis induction. Interestingly the ripoptosome triggers necroptopsis �programmed necrosis� mediated through RIP� sig­ naling [���]. The extrinsic pathway of apoptosis is a�rogated through several mechanisms� including the up­regula­ tion of the inhi�itors of apoptosis proteins such as cIAP or XIAP. Up­regulation of these inhi�itors of apopto­ sis molecules will drive the TNF­α pathway towards NF­κB activation in the same manner as descri�ed a�ove. Apart from inhi�ition �y the IAP family� recent data indicate that IL­�/�TAT� signaling can override apoptotic signals �y activating pro­survival proteins �BCL­�� BCL­xL� as well as cyclin D [9�]. TRAIL­ and FA�­mediated apoptosis pathways are very similar to one another in that these trimeric ligands �ind their specific cognate receptors towards apoptosis induc­ tion. TRAIL �inds to the DR �/DR� receptors which leads to receptor oligomerization in the plasma mem�rane� some groups suggest that these receptors oligomerize in the lipid rafts of the plasma mem�rane [9�]. Once the receptors oligomerize there is recruitment of adap­ tor protein FADD. FADD �inding to the TRAIL receptor leads to initiator caspase­8 recruitment to form the death inducing signaling complex �DI�C�. Following DI�C formation procaspase­8 �ecomes autocata­ lytically active� once active caspase­8 is processed into the active p�8 and p�� su�units via two cleavage events. Once processed the p�8 and p�� dimers can oligomerize with other p�8/p�� dimers to form active heterotetramers� that cleaves specific targets such as HDAC� [9�]� and executioner caspase­� and ­� which fully induce the apoptotic response [9�]. Tumor cells utilize various mechanisms to inactivate the extrinsic pathway of apoptosis; that �e down­ regulation of death receptors or up­regulation of decoy receptors [9�]. For TRAIL� its cognate receptors con­ sist of death receptor­� or ­� �DR­�� ­��� as a protec­ tive measure� the cell also expresses decoy receptors Dcr� and Dcr� as an effort to prevent unintended apoptosis induction through TRAIL �inding to the death receptors [98]. In addition to receptor or decoy mediated inhi�ition� the extrinsic pathway is inhi�ited �y over­expression of BCL­�� BCL­xL� cIAP and XIAP anti­apoptotic proteins [99� ���]. �tudies in mouse models demonstrated that TRAIL targets cancer cells and not healthy non­neoplastic cells [���]. This specificity renders TRAIL a valua�le chemotherapeutic agent due to the limited side effects and TRAIL protein can �e synthesized via standard protein purification methods [��]. TRAIL C­terminal conjugation can ex­ tend TRAIL half­life �y �� hours allowing it to �e used for in vitro and in vivo experiments. For clinical trial and treatment applications companies� like Human Genome �ciences �Rockville MD� U�A� have gene­ rated TRAIL receptor activating anti�odies with the intent to extend TRAIL half­life. These companies were successful in generating TRAIL receptor anti�odies as evidenced �y several in vitro and in vivo studies that analyzed TRAIL anti�odies� mapatumuma� and lexa­ tumuma� indicating their a�ility to induce apoptosis [���� ���]. Additional pre­clinical studies have com­ �ined TRAIL with existing chemotherapeutic agents� including phytoshingosine �impacts sphingolipid me­ ta�olism� [���]� doxoru�icin [���]� docetaxel [���] and paclitaxel [���] all of which with much promise� suggesting that TRAIL should �e investigated further as a chemotherapeutic strategy. There is a clinical trial in progress involving the com�ination of TRAIL and VEGF inhi�itor� �evacizuma� �Clinical trial identifier� NCT����8����. CASPASES IN CONTROL OF APOPTOSIS Caspases are a family of cysteine proteases which contain cysteine residue at their active site and cleave their su�strate at position next to aspartate residue. A very unique family of enzymes which remain active right from early stages of em�ryonic development till the death of organism. The entire group of mam­ malian caspases is divided into three different groups on the �asis of their prodomains and specific func­ tion they play in the in several different pathways� including� inflammatory� development� and apoptotic pathways. Although each caspase serves a different purpose there are several similarities in cleavage� the proform is cleaved into a large catalytically ac­ tive su�unit and a small su�unit as shown for the critical apoptotic caspase­8. Caspase­� and ­� play a role in inflammation [��8� ��9]. The endoplasmic reticulum �ER� stress response pathways� unfolded protein response �UPR�� or ER associated degradation �ERAD� are mediated through caspase­�� eventu­ ally leading apoptosis induction through the intrinsic pathway. ER is a critical cellular organelle whose primary function is to ensure proteins are properly ��� Experimental Oncology ��� �������� ���� ��eptem�er� folded �efore export into the Golgi apparatus [���]. The protein folding machinery consists of several components that work in concert to ensure proper protein folding. However� when the ER is overwhelmed with polypeptides that are incapa�le of �eing folded correctly� three sensors� IRE­�� PERK� and ATF� trig­ ger the UPR [���]. As high ER stress persists� CHOP expression is markedly increased� down­regulating the pro­survival BCL­� family mem�ers� BCL­� and BCL­ xL allowing for BAX and BAD expression and activity to increase [���]. Alternative intrinsic pathway induc­ tion mechanisms involve the activation of caspase­�� ­�� and ­�� [���]� contri�uting to caspase­9 process­ ing either through disrupting the mitochondria [���] or through APAF­� independent mechanisms [���]. Caspase­� induces the intrinsic pathway of apoptosis either through Bid cleavage thus leading to intrinsic pathway activation via the opening of the MOMP re­ leasing cytochrome c facilitating apoptosome forma­ tion or through caspase­�� PIDD� and adaptor protein RAIDD �ind and form PIDDosome [���]. Compared to healthy cells� tumor cells have a marked increase in protein synthesis as well as an over­production of misfolded or unfolded protein in the ER� resulting in extremely high ER stress levels. Therefore treatment strategies focus on apoptosis induction via elevating ER stress using chemotherapeutics such as velcade [���]. Velcade is designed to �lock the ��� protea­ some and once inhi�ited� UPR response mechanisms �ecome impaired leading to apoptosis induction [��8]. To circumvent proteasome inhi�ition� cells activate lysosomal pathways as an alternate mechanism for protein clearance. Exploitation of this mechanism as an anti­cancer strategy involves the use of vel­ cade in com�ination with lysosomal inhi�itor� tu�acin �an HDAC� inhi�itor that �lock aggresome formation�� that results apoptosis [��9]. The major players involved with the intrinsic pathway of apoptosis induction� are cytochrome c� APAF­�� and caspase­9 which form the apoptosome. Caspase­9 is su�sequently processed into its active p�� and p�9 su�units [���] and capa�le of cleaving executioner caspase­�/­�. Cancer circum­ vents the intrinsic pathway activation �y engaging vari­ ous mechanisms� such as loss of caspase­9 activation via the involvement of the BCL­� family mem�ers� BCL­ �� BCL­xL or XIAP �inding� or �y �locking apoptosome formation through pro­survival signals� preventing the opening of the mitochondria and �locking the release of cytochrome c [���]. Of direct clinical significance is evidence that tumors from patients with colorectal� lung� or gastric cancer� har�or different point muta­ tions in caspase­9� that render it inactive and incapa�le of inducing apoptosis [���]. The mechanistic landscape of caspase activation during the tumor cellular demise� takes intriguing functional turns during cancer initiation and progres­ sion �Fig. ��. Executioner caspase­� and ­� �effector caspases� are processed into active su�units and re­ sponsi�le for the execution of the apoptosis program through the cleavage of caspase­activated DNase which then translocates to the nucleus and cleaves DNA [���]. Caspase­� propagates and amplifies the apoptosis signal through a loop that leads to cas­ pase­9 cleavage thus further propagating the apop­ totic cascade [���]. Loss of caspase­� expression pro­ motes tumorigenesis [���]� while caspase­� is down regulated in cancer [���]. Caspase­�� is an initiator caspase recruited to the DI�C like caspase­8 and is ca­ pa�le of inducing apoptosis in certain caspase­8 de­ ficient tumor cells [���] however� caspase­�� is not sufficient to induce apoptosis in the a�sence of cas­ pase­8 in other cancer types [��8]. Fig. 3. General cleavage events for critical apoptotic related caspases. Caspase­8 and ­�� are larger than other caspases �ecause they contain DED domains responsi�le for �inding to the DI�C complex CASPASE-8 IN DEATH RECEPTOR INDEPENDENT AND DEPENDENT PATHWAYS Intriguing new evidence supports a role for cas­ pase­8 in non­apoptotic signaling pathways. �tupack et al. ����9� reported that caspase­8 in neuro�las­ toma cell lines plays a role in mediating focal adhe­ sion complex formation and cellular migration [��9]. Earlier studies defined a pathway� similar to anoikis phenomenon� termed intergin mediated death [���]. Caspase­8 is phosphorylated on tyrosine residue �8� via �RC kinase and is associated with FAK and CNB� and upon its recruitment activates the calpain family of proteases that cleave talin [���]. �ignificantly enough� the N­terminal cleavage product of talin� the FERM� is an integrin �inding domain which facili­ tates cell migration [��9]� indirectly implicating cas­ pase­8 in mediating metastasis via the focal adhesion complex [��9]. Moreover� Ra��� a critical modulator of caspase­8 action in cell migration [���]� is function­ Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ��� ally involved in migration� either through lamellipodia formation [���]� β� integrin �inding� or through actin cytoskeleton [���]. �everal lines of evidence support the involvement of caspase­8 in EGF signaling pathways inducing ERK activation through the incorporation of cas­ pase­8 in �RC containing complexes. This work iden­ tified through a RXDLL motif found within the DED of caspase­8 pro­domain� this allows caspase­8 to as­ sociate with �RC although the data did not show any evidence that caspase­8 phosphorylation was required for �RC association and EGF pathway activation [���]. Caspase­8 as a critical player for extrinsic pathway activation has long �een considered a tumor sup­ pressor molecule. Indeed caspase­8 deficient cells are insensitive to death ligand stimulus and cannot induce apoptosis through the extrinsic pathway� thus facilitating tumorigenic transformation and conferring therapeutic resistance [���]. Human cancer cells regulate caspase­8 activity through a variety of mecha­ nisms� one mechanism is caspase­8 partial or whole gene deletion� [���] or gene methylation. For example� medullo�lastoma pediatric neuro�lastoma tumors down­regulate caspase­8 expression through methy­ lation of the caspase­8 promoter there�y inhi�iting caspase­8 transcription thus preventing protein trans­ lation and expression [��8]. �tudies involving a screen across multiple cancer types identified frame shift and missense mutations in caspase­8 [��9]� which altered amino acid compositions in the DED domain� a domain a�solutely critical for caspase­8 recruitment to the DI�C and initiating cleavage events [��9]. Moreover� mutations were found in the p�8 catalytically active su�unit and the p�� regions validation of the screen results revealed that most of the mutants severely diminished apoptosis induction in gastric carcinomas [��9]. Upon recruitment to the DI�C caspase­8 un­ dergoes two cleavage events� the first cleavage event occurs at aspartic acid residue �8� in the p�� su�unit� giving rise to the p��/�� intermediate which is �ound at the DI�C. This cleavage event is followed �y a se­ cond cleavage at aspartic acid residues ���� ��� which then release caspase­8 from the DI�C into the cy­ tosol �Fig. ��. Pioneering work �y Dr. Marcus Peter defined how the DI�C components were assem�led at the plasma mem�rane through TRAIL and/or FA� receptor and FADD palmitylation [���� ���]. Further studies provided evidence towards DI�C mediated caspase­8 processing [���� ���]. Additional studies focusing on DI�C formation �y Marcus Peter’s la� identified that c­FLIP was a specific inhi�itor of cas­ pase­8 DI�C recruitment and activation [���]. �u�se­ quent work identified c­FLIP isoforms that �lock gene induction as well as processing of caspase­8 [���]. Besides c­FLIP� XIAP and cIAP are also capa�le of �locking caspase­8 activation [���]. Emerging evidence �y two independent groups� Jin et al. [���]� and Peng et al. [��8]� provided new insights regard­ ing caspase­8 polyu�iquitination. Jin and colleagues provided evidence indicating that E� ligase CUL� me­ diated polyu�iquitination led to caspase­8 incorpora­ tion into an aggresome. Caspase­8 polyu�iquitination however in the context of EGR signaling� is mediated through R�K� activity [��8]� engaging two E� ligases� �iah� and PO�H� in prostate cancer cells [��9]� thus exerting a regulatory role on caspase­8 activity down­ stream of DI�C and caspase­8 processing [��9]. The com�ination of proteasome inhi�ition with TRAIL takes an all­lethal impact� as it induces apoptosis in TRAIL­ resistant prostate cancer cells in vitro and in vivo [��]. Moreover� com�ination of TRAIL and velcade leads to caspase­8 p�8 su�unit sta�ilization [��� ��� ���]� implicating caspase­8 degradation �eing controlled �y the ��� proteasome. In summary� strategies to circumvent therapeutic resistance �y restoration of apoptotic pathways� utiliz­ ing single apoptosis inducing agents such as TRAIL� separately or in com�ination with other chemothera­ peutics� provide new promise in the clinical manage­ ment of cancer patients. These apoptosis inducing agents may also �e capa�le of inducing apoptosis� regardless of the tumor hormonal milieu and driven �y the cellular interactions with the tumor microenvi­ ronment. In that regard com�ination of proteasome inhi�itor and TRAIL is capa�le cleaving and activating caspase­8 in either androgen­dependent� or androgen independent prostate cancer �CRPC�. The clinical knowledge of microtu�ulin­targeted chemotherapy �taxanes� as the only effective treatment for CRPC� calls for the need to understand the mechanisms of action of this drug in order to augment its therapeu­ tic efficacy and overcome the therapeutic resistance to its antitumor actions in a large num�er of prostate cancer patients. Profiling the caspase activation status in response to taxane­�ased chemotherapy �in com­ �ination with apoptosis­driven agents� and in the context of cytoskeleton organization� provides excit­ ing new platforms for therapeutic optimization driving apoptosis to its full execution in a su�set of tumors and ultimately impacting patient survival. ACKNOWLEDGEMENTS The authors wish to acknowledge Drs. �teven �chwarze� Vivek Rangnekar and �tephen �trup for useful discussions and the administrative assistance of Lorie Howard. The studies have �een supported �y grants from the Department of Defense �U�AMRMC PC�������� the James F. 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