BCL-2 protein family: attractive targets for cancer therapy

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Abstract

Acquired resistance to cell death is a hallmark of cancer. The BCL-2 protein family members play important roles in controlling apoptotic cell death. Abnormal over-expression of pro-survival BCL-2 family members or abnormal reduction of pro-apoptotic BCL-2 family proteins, both resulting in the inhibition of apoptosis, are frequently detected in diverse malignancies. The critical role of the pro-survival and pro-apoptotic BCL-2 family proteins in the regulation of apoptosis makes them attractive targets for the development of agents for the treatment of cancer. This review describes the roles of the various pro-survival and pro-apoptotic members of the BCL-2 protein family in normal development and organismal function and how defects in the control of apoptosis promote the development and therapy resistance of cancer. Finally, we discuss the development of inhibitors of pro-survival BCL-2 proteins, termed BH3-mimetic drugs, as novel agents for cancer therapy.

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Hallmarks of Cancer: New Dimensions

Douglas Hanahan (2022)

The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity of cancer phenotypes and genotypes into a provisional set of underlying principles. As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refinements. Herein, the prospect is raised that phenotypic plasticity and disrupted differentiation is a discrete hallmark capability, and that nonmutational epigenetic reprogramming and polymorphic microbiomes both constitute distinctive enabling characteristics that facilitate the acquisition of hallmark capabilities. Additionally, senescent cells, of varying origins, may be added to the roster of functionally important cell types in the tumor microenvironment. SIGNIFICANCE: Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy. Ever more powerful experimental and computational tools and technologies are providing an avalanche of "big data" about the myriad manifestations of the diseases that cancer encompasses. The integrative concept embodied in the hallmarks of cancer is helping to distill this complexity into an increasingly logical science, and the provisional new dimensions presented in this perspective may add value to that endeavor, to more fully understand mechanisms of cancer development and malignant progression, and apply that knowledge to cancer medicine.

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The landscape of somatic copy-number alteration across human cancers

Rameen Beroukhim, Craig H. Mermel, Dale Porter … (2010)

A powerful way to discover key genes playing causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here, we report high-resolution analyses of somatic copy-number alterations (SCNAs) from 3131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across multiple cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-κB pathway. We show that cancer cells harboring amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend upon expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in multiple cancer types.

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Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy.

Peter Czabotar, Guillaume Lessene, Andreas Strasser … (2014)

The BCL-2 protein family determines the commitment of cells to apoptosis, an ancient cell suicide programme that is essential for development, tissue homeostasis and immunity. Too little apoptosis can promote cancer and autoimmune diseases; too much apoptosis can augment ischaemic conditions and drive neurodegeneration. We discuss the biochemical, structural and genetic studies that have clarified how the interplay between members of the BCL-2 family on mitochondria sets the apoptotic threshold. These mechanistic insights into the functions of the BCL-2 family are illuminating the physiological control of apoptosis, the pathological consequences of its dysregulation and the promising search for novel cancer therapies that target the BCL-2 family.

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Author and article information

Contributors

Gemma L Kelly: gkelly@wehi.edu.au

Journal

Journal ID (nlm-ta): Apoptosis

Journal ID (iso-abbrev): Apoptosis

Title: Apoptosis

Publisher: Springer US (New York )

ISSN (Print): 1360-8185

ISSN (Electronic): 1573-675X

Publication date (Electronic): 7 November 2022

Publication date PMC-release: 7 November 2022

Publication date (Print): 2023

Volume: 28

Issue: 1-2

Pages: 20-38

Affiliations

[1 ]GRID grid.1042.7, ISNI 0000 0004 0432 4889, Blood Cells and Blood Cancer Division, , Walter and Eliza Hall Institute of Medical Research, ; Melbourne, VIC Australia

[2 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Department of Medical Biology, , University of Melbourne, ; Melbourne, VIC Australia

Article

Publisher ID: 1780

DOI: 10.1007/s10495-022-01780-7

PMC ID: 9950219

PubMed ID: 36342579

SO-VID: 241ff6e3-39e8-44c9-85c4-982d9bf5b649

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date accepted : 10 October 2022

Funding

Funded by: University of Melbourne

Open Access :

Open Access funding enabled and organized by CAUL and its Member Institutions

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ScienceOpen disciplines: Molecular biology

Keywords: apoptosis,bcl-2 protein family,pro-survival bcl-2 proteins,pro-apoptotic bcl-2 family members,bh3-only proteins,bh3-mimetic drugs

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ScienceOpen disciplines: Molecular biology

Keywords: apoptosis, bcl-2 protein family, pro-survival bcl-2 proteins, pro-apoptotic bcl-2 family members, bh3-only proteins, bh3-mimetic drugs

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BCL-2 protein family: attractive targets for cancer therapy

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Higher order chromatin architecture

Most cited references 234

Hallmarks of Cancer: New Dimensions

The landscape of somatic copy-number alteration across human cancers

Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy.

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