Why do BCL-2 inhibitors work and where should we use them in the clinic?

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Abstract

Intrinsic apoptosis is controlled by the BCL-2 family of proteins but the complexity of intra-family interactions makes it challenging to predict cell fate via standard molecular biology techniques. We discuss BCL-2 family regulation and how to determine cells’ readiness for apoptosis and anti-apoptotic dependence. Cancer cells often adopt anti-apoptotic defense mechanisms in response to oncogenic stress or anti-cancer therapy. However, by determining their anti-apoptotic addiction, we can use novel BH3 mimetics to overwhelm this apoptotic blockade. We outline the development and uses of these unique anti-apoptotic inhibitors and how to possibly combine them with other anti-cancer agents using dynamic BH3 profiling (DBP) to improve personalized cancer treatment.

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Most cited references 90

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Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked.

J Yang, X Liu, K Bhalla … (1997)

Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria. Overexpression of Bcl-2 prevents cells from undergoing apoptosis in response to a variety of stimuli. Cytosolic cytochrome c is necessary for the initiation of the apoptotic program, suggesting a possible connection between Bcl-2 and cytochrome c, which is normally located in the mitochondrial intermembrane space. Cells undergoing apoptosis were found to have an elevation of cytochrome c in the cytosol and a corresponding decrease in the mitochondria. Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis. Thus, one possible role of Bcl-2 in prevention of apoptosis is to block cytochrome c release from mitochondria.

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Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death.

Z Oltvai, C Milliman, S Korsmeyer (1993)

Bcl-2 protein is able to repress a number of apoptotic death programs. To investigate the mechanism of Bcl-2's effect, we examined whether Bcl-2 interacted with other proteins. We identified an associated 21 kd protein partner, Bax, that has extensive amino acid homology with Bcl-2, focused within highly conserved domains I and II. Bax is encoded by six exons and demonstrates a complex pattern of alternative RNA splicing that predicts a 21 kd membrane (alpha) and two forms of cytosolic protein (beta and gamma). Bax homodimerizes and forms heterodimers with Bcl-2 in vivo. Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line. Overexpressed Bax also counters the death repressor activity of Bcl-2. These data suggest a model in which the ratio of Bcl-2 to Bax determines survival or death following an apoptotic stimulus.

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Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis.

E Oda, R Ohki, H Murasawa … (2000)

A critical function of tumor suppressor p53 is the induction of apoptosis in cells exposed to noxious stresses. We report a previously unidentified pro-apoptotic gene, Noxa. Expression of Noxa induction in primary mouse cells exposed to x-ray irradiation was dependent on p53. Noxa encodes a Bcl-2 homology 3 (BH3)-only member of the Bcl-2 family of proteins; this member contains the BH3 region but not other BH domains. When ectopically expressed, Noxa underwent BH3 motif-dependent localization to mitochondria and interacted with anti-apoptotic Bcl-2 family members, resulting in the activation of caspase-9. We also demonstrate that blocking the endogenous Noxa induction results in the suppression of apoptosis. Noxa may thus represent a mediator of p53-dependent apoptosis.

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Author and article information

Journal

Journal ID (nlm-ta): Cell Death Differ

Journal ID (iso-abbrev): Cell Death Differ

Title: Cell Death and Differentiation

Publisher: Nature Publishing Group

ISSN (Print): 1350-9047

ISSN (Electronic): 1476-5403

Publication date (Print): January 2018

Publication date (Electronic): 27 October 2017

Publication date PMC-release: 1 January 2018

Volume: 25

Issue: 1

Pages: 56-64

Affiliations

[1 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School , Boston, MA 02215, USA

Author notes

[* ]Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School , Mayer 426, 450 Brookline Ave, Boston, MA, USA. Tel: +1 617 386 9406. E-mail: joan_montero@ 123456dfci.harvard.edu

[* ]Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School , Mayer 430, 450 Brookline Ave, Boston, MA, USA. Tel: +1 617 632 2348. Email: Anthony_letai@ 123456dfci.harvard.edu

[2]

Current address: Institute for Bioengineering of Catalonia (IBEC), Helix building, A11-A13 lab | C/ Baldiri Reixac 15-21, Barcelona, 08028. Tel. +34 93 403 99 56; E-mail: jmontero@ 123456ibecbarcelona.eu

Article

Publisher Item ID: cdd2017183

DOI: 10.1038/cdd.2017.183

PMC ID: 5729538

PubMed ID: 29077093

SO-VID: b19eeeb7-ac14-46c7-9118-403481a780df

License:

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

History

Date received : 04 June 2017

Date revision received : 14 August 2017

Date accepted : 31 August 2017

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Why do BCL-2 inhibitors work and where should we use them in the clinic?

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Stress signalling in stem cells

Most cited references 90

Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked.

Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death.

Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis.

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