Inducing death in tumor cells: roles of the inhibitor of apoptosis proteins

The heterogeneous group of diseases collectively termed cancer results not just from aberrant cellular proliferation but also from a lack of accompanying homeostatic cell death. Indeed, cancer cells regularly acquire resistance to programmed cell death, or apoptosis, which not only supports cancer progression but also leads to resistance to therapeutic agents. Thus, various approaches have been undertaken in order to induce apoptosis in tumor cells for therapeutic purposes. Here, we will focus our discussion on agents that directly affect the apoptotic machinery itself rather than on drugs that induce apoptosis in tumor cells indirectly, such as by DNA damage or kinase dependency inhibition. As the roles of the Bcl-2 family have been extensively studied and reviewed recently, we will focus in this review specifically on the inhibitor of apoptosis protein (IAP) family. IAPs are a disparate group of proteins that all contain a baculovirus IAP repeat domain, which is important for the inhibition of apoptosis in some, but not all, family members. We describe each of the family members with respect to their structural and functional similarities and differences and their respective roles in cancer. Finally, we also review the current state of IAPs as targets for anti-cancer therapeutics and discuss the current clinical state of IAP antagonists.

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Anticancer Activity of Diosgenin and its Semi-synthetic Derivatives: Role in Autophagy Mediated Cell Death and Induction of Apoptosis

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521666210105111224 ◽

2021 ◽

Vol 21 ◽

Author(s):

Nivedita Bhardwaj ◽

Nancy Tripathi ◽

Bharat Goel ◽

Shreyans K. Jain

Keyword(s):

Cell Death ◽

Cancer Treatment ◽

Anticancer Activity ◽

Tumor Cells ◽

Cancer Progression ◽

Rational Approach ◽

Potential Candidate ◽

Potential Implication ◽

Apoptosis Protein ◽

Synthetic Derivatives

: During cancer progression, the unrestricted proliferation of cells is supported by the impaired cell death response provoked by certain oncogenes. Both autophagy and apoptosis are the signaling pathways of cell death, which are targeted for cancer treatment. Defects in apoptosis result in reduced cell death and ultimately tumor progression. The tumor cells lacking apoptosis phenomena are killed by ROS- mediated autophagy. The autophagic programmed cell death requires apoptosis protein for inhibiting tumor growth; thus, the interconnection between these two pathways determines the fate of a cell. The cross-regulation of autophagy and apoptosis is an important aspect to modulate autophagy, apoptosis and to sensibilise apoptosis-resistant tumor cells under metabolic stress and might be a rational approach for drug designing strategy for the treatment of cancer. Numerous proteins involved in autophagy have been investigated as the druggable target for anticancer therapy. Several compounds of natural origin have been reported, to control autophagy activity through the PI3K/Akt/mTOR key pathway. Diosgenin, a steroidal sapogenin has emerged as a potential candidate for cancer treatment. It induces ROS-mediated autophagy, inhibits PI3K/Akt/mTOR pathway, and produces cytotoxicity selectively in cancer cells. This review aims to focus on optimal strategies using diosgenin to induce apoptosis by modulating the pathways involved in autophagy regulation and its potential implication in the treatment of various cancer. The discussion has been extended to the medicinal chemistry of semi-synthetic derivatives of diosgenin exhibiting anticancer activity.

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Translational Induction of the Inhibitor of Apoptosis Protein HIAP2 during Endoplasmic Reticulum Stress Attenuates Cell Death and Is Mediated via an Inducible Internal Ribosome Entry Site Element

Journal of Biological Chemistry ◽

10.1074/jbc.m308737200 ◽

2004 ◽

Vol 279 (17) ◽

pp. 17148-17157 ◽

Cited By ~ 89

Author(s):

Dinesh Warnakulasuriyarachchi ◽

Sonia Cerquozzi ◽

Herman H. Cheung ◽

Martin Holcík

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Endoplasmic Reticulum Stress ◽

Internal Ribosome Entry Site ◽

Inhibitor Of Apoptosis ◽

Entry Site ◽

Internal Ribosome Entry ◽

Inhibitor Of Apoptosis Protein ◽

Apoptosis Protein

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Pseudomonas aeruginosaDelays Kupffer Cell Death via Stabilization of the X-Chromosome-Linked Inhibitor of Apoptosis Protein

The Journal of Immunology ◽

10.4049/jimmunol.179.1.505 ◽

2007 ◽

Vol 179 (1) ◽

pp. 505-513 ◽

Cited By ~ 7

Author(s):

Alix Ashare ◽

Martha M. Monick ◽

Amanda B. Nymon ◽

John M. Morrison ◽

Matthew Noble ◽

...

Keyword(s):

Cell Death ◽

X Chromosome ◽

Kupffer Cell ◽

Inhibitor Of Apoptosis ◽

Inhibitor Of Apoptosis Protein ◽

Apoptosis Protein

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The Immuno-Modulatory Effects of Inhibitor of Apoptosis Protein Antagonists in Cancer Immunotherapy

Cells ◽

10.3390/cells9010207 ◽

2020 ◽

Vol 9 (1) ◽

pp. 207 ◽

Cited By ~ 3

Author(s):

Jessica Michie ◽

Conor J. Kearney ◽

Edwin D. Hawkins ◽

John Silke ◽

Jane Oliaro

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Tumour Progression ◽

Mitochondrial Protein ◽

Immune Checkpoint Blockade ◽

Oncolytic Viruses ◽

Inhibitor Of Apoptosis ◽

T Cell Therapy ◽

Apoptosis Protein ◽

Smac Mimetics

One of the hallmarks of cancer cells is their ability to evade cell death via apoptosis. The inhibitor of apoptosis proteins (IAPs) are a family of proteins that act to promote cell survival. For this reason, upregulation of IAPs is associated with a number of cancer types as a mechanism of resistance to cell death and chemotherapy. As such, IAPs are considered a promising therapeutic target for cancer treatment, based on the role of IAPs in resistance to apoptosis, tumour progression and poor patient prognosis. The mitochondrial protein smac (second mitochondrial activator of caspases), is an endogenous inhibitor of IAPs, and several small molecule mimetics of smac (smac-mimetics) have been developed in order to antagonise IAPs in cancer cells and restore sensitivity to apoptotic stimuli. However, recent studies have revealed that smac-mimetics have broader effects than was first attributed. It is now understood that they are key regulators of innate immune signalling and have wide reaching immuno-modulatory properties. As such, they are ideal candidates for immunotherapy combinations. Pre-clinically, successful combination therapies incorporating smac-mimetics and oncolytic viruses, as with chimeric antigen receptor (CAR) T cell therapy, have been reported, and clinical trials incorporating smac-mimetics and immune checkpoint blockade are ongoing. Here, the potential of IAP antagonism to enhance immunotherapy strategies for the treatment of cancer will be discussed.

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Diablo Promotes Apoptosis by Removing Miha/Xiap from Processed Caspase 9

The Journal of Cell Biology ◽

10.1083/jcb.152.3.483 ◽

2001 ◽

Vol 152 (3) ◽

pp. 483-490 ◽

Cited By ~ 128

Author(s):

Paul G. Ekert ◽

John Silke ◽

Christine J. Hawkins ◽

Anne M. Verhagen ◽

David L. Vaux

Keyword(s):

Cell Death ◽

Cytochrome C ◽

Caspase 3 ◽

Direct Interaction ◽

Inhibitor Of Apoptosis ◽

Caspase 9 ◽

Inhibitor Of Apoptosis Protein ◽

Grim Reaper ◽

Apoptosis Protein ◽

Mammalian Protein

MIHA is an inhibitor of apoptosis protein (IAP) that can inhibit cell death by direct interaction with caspases, the effector proteases of apoptosis. DIABLO is a mammalian protein that can bind to IAPs and antagonize their antiapoptotic effect, a function analogous to that of the proapoptotic Drosophila molecules, Grim, Reaper, and HID. Here, we show that after UV radiation, MIHA prevented apoptosis by inhibiting caspase 9 and caspase 3 activation. Unlike Bcl-2, MIHA functioned after release of cytochrome c and DIABLO from the mitochondria and was able to bind to both processed caspase 9 and processed caspase 3 to prevent feedback activation of their zymogen forms. Once released into the cytosol, DIABLO bound to MIHA and disrupted its association with processed caspase 9, thereby allowing caspase 9 to activate caspase 3, resulting in apoptosis.

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