BCL-2 Family Pathway

Overview

The B-cell lymphoma 2 (BCL-2) family is composed of anti- and pro-apoptotic proteins that function to regulate the intrinsic pathway of apoptosis, or programmed cell death, and help maintain tissue homeostasis.1,2

The BCL-2 family is composed of anti- and pro-apoptotic proteins that function to regulate the intrinsic pathway of apoptosis.1,2

  • Anti-apoptotic members: BCL-2, BCL-XL, BFL-1/A1, BCL-W and MCL-1.3
  • Pro-apoptotic members: BAX, BAK, BIM, BID, BOK, BAD, HRK, PUMA and NOXA.2,4
  • When working in concert, these proteins regulate apoptosis to maintain normal tissue homeostasis.1,5

The BCL-2 family of proteins controls cell death primarily by direct binding interactions that regulate mitochondrial outer membrane permeabilization (MOMP), a process leading to the irreversible release of intermembrane space proteins, subsequent caspase activation and apoptosis.6

  • The affinities and relative abundance of the BCL-2 family proteins dictate interactions between anti-apoptotic and pro-apoptotic BCL-2 family proteins that regulate MOMP.6

Implications in cancer

Acquired resistance to apoptosis is a hallmark of most, if not all types of cancer.7

  • In cancer, apoptosis evasion through dysregulation of specific BCL-2 family genes is a recurring event.8
  • Dysregulation of the apoptotic pathways can not only promote tumorigenesis, but can also render cancer cells resistant to conventional anti-cancer agents, since chemotherapy- and radiotherapy-induced killing of cancer cells is mainly mediated through activation of apoptosis.2

Overexpression of anti-apoptotic BCL-2 family proteins (BCL-2, BCL-XL, BFL-1/A1, BCL-W and MCL-1) disrupts the dynamic balance of anti- and pro-apoptotic proteins, which may promote cancer cell survival.2,5

  • The overexpression of these proteins is seen in a wide variety of hematologic malignancies and solid tumors.2,9
  • The heterogeneity among tumors, even of the same type, necessitates a continued effort to further investigate mechanisms of apoptosis dysregulation in distinct cancer cell types.2

Strategies to inhibit anti-apoptotic BCL-2 proteins include reducing protein expression by targeting the corresponding mRNA with an antisense oligonucleotide as well as blocking anti-apoptotic activity by targeting at the protein level.2,5

  • There is interest in developing drugs that mimic the action of the BH3 motif by binding to one or more of the BCL-2-like anti-apoptotic proteins and triggering apoptosis.5

Oncogenic Expression

The majority of tumors have defects in the p53 pathway and many overexpress BCL-2 or a close relative, such as BCL-XL.2

  • Most CLLs, FLs, and MCLs were found to have moderate to high expression of BCL-2 and BCL-XL.9
  • Amplification and overexpression of MCL-1 have been reported in various human tumors, including hematologic malignancies and solid tumors.10
  1. Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 2003;22:8590-8607.
  2. Plati J, Bucur O, Khosravi-Far R. Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb). 2011;3:279-296.
  3. Trudel S, Stewart AK, Li Z, et al. The Bcl-2 family protein inhibitor, ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan. Clin Cancer Res. 2007;13(2):621-629.
  4. Davids MS, Letai A. Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol. 2012;30(25):3127-3135.
  5. Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007;26:1324-1337.
  6. Kale J, et al. BCL-2 family proteins: changing partners in the dance towards death. Cell Death and Differentiation. 2018;25:65–80.
  7. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.
  8. Ashkenazi A, et al. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov. . 2017;16:273–284. (image)
  9. Agarwal B, et al. Bcl-2 family of proteins in indolent B-cell non-Hodgkin's lymphoma: study of 116 cases. Am J Hematol. 2002 Aug;70(4):278-82.
  10. Zhang X, et al. Targeting anti-apoptotic BCL-2 family proteins for cancer treatment. Future Med. Chem. 2020;12(7):563–565.

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