Proper execution of cell death ensures normal biological processes, and its dysregulation causes human illness, ranging from cancer to neurodegenerative disorders. Apoptosis is a regulated form of cell death. Impairment of apoptosis is not only central to cancer development but also renders tumors refractory to cytotoxic therapy. Hence, further elucidation of the apoptotic signaling framework will not only help understand how cancer cells escape apoptotic checkpoints but also contribute to the development of rationally designed targeted cancer therapy. The BCL-2 family proteins govern cell death-versus-survival decisions at the mitochondria and can be divided into three subfamilies: (1) multidomain antiapoptotic BCL-2, BCL-XL and MCL-1;(2) multidomain proapoptotic BAX and BAK;and (3) proapoptotic BH3-only molecules (BH3s). BH3s relay upstream apoptotic signals to promote apoptosis by either activating BAX/BAK or inactivating BCL-2/BCL-XL/MCL-1. Genetic loss-of-function studies reveal an essential axis of upstream """"""""activator"""""""" BH3s and downstream BAX/BAK in activating mitochondrion-dependent apoptosis. In response to apoptotic signals, the """"""""activator"""""""" BH3s, including BID, BIM and PUMA, trigger the homo-oligomerization of BAX and BAK to permeabilize mitochondria, leading to the efflux of cytochrome c to the cytosol for caspase activation. We recently discovered a novel mechanism by which BH3s activate BAX/BAK- dependent mitochondrial permeabilization. We propose to elucidate this novel mechanism and reclassify BH3s based on their mechanisms in initiating cell death. Activation of BAX/BAK by BH3s not only triggers APAF-1-mediated caspase activation but also initiates caspase- independent cell death. Further characterization of this novel form of cell death holds promises for the future development of anti-cancer therapeutics that targets cancer cells with defective caspase activation. We are also pursing whether BAX and BAK reside in different protein complexes to differentially regulate caspase-dependent and -independent cell death programs. Overall, our goal is to build a comprehensive proapoptotic BCl-2 signaling network in activating mitochondrion-dependent cell death programs, which offers common ground for therapeutic interventions.

Public Health Relevance

The ability of cancer cells to evade cell death constitutes one of the hallmarks of cancer. Hence, studies of fundamental cell death mechanisms provide unique opportunities for molecularly designed cancer therapeutics. The BCL-2 family proteins are the central regulators of cell death. We propose to investigate the molecular mechanisms by which BCL-2 family proteins regulate cell death with the hope that our study will enable novel targeted therapeutic strategies that specifically trigger cell death in cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA125562-06A1
Application #
8697656
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Salnikow, Konstantin
Project Start
2006-12-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
$353,954
Indirect Cost
$151,454
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Mandal, Tirtha; Shin, Seungjin; Aluvila, Sreevidya et al. (2016) Assembly of Bak homodimers into higher order homooligomers in the mitochondrial apoptotic pore. Sci Rep 6:30763
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Kim, Hyungjin; Tu, Ho-Chou; Ren, Decheng et al. (2009) Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol Cell 36:487-99

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