BCL-2 family deregulation in colorectal cancer: potential for BH3 mimetics in therapy

Apoptosis. 2020 Jun;25(5-6):305-320. doi: 10.1007/s10495-020-01601-9.

Abstract

Apoptosis is a form of programmed cell death that is essential for tissue homeostasis. De-regulation of the balance between proliferation and apoptosis contributes to tumor initiation. Particularly in the colon where apoptosis is a crucial process in intestinal turnover, inhibition of apoptosis facilitates transformation and tumor progression. The BCL-2 family of proteins are key regulators of apoptosis and have been implicated in colorectal cancer (CRC) initiation, progression and resistance to therapy. In this review we outline the current knowledge on the BCL-2 family-regulated intrinsic apoptosis pathway and mechanisms by which it is de-regulated in CRC. We further review BH3 mimetics as a therapeutic opportunity to target this pathway and evaluate their potential for CRC treatment.

Keywords: Apoptosis; BCL-2 family; BH3 mimetics; Colorectal cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • BH3 Interacting Domain Death Agonist Protein / genetics
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Molecular Mimicry
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction
  • bcl-2 Homologous Antagonist-Killer Protein / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BAK1 protein, human
  • BAX protein, human
  • BBC3 protein, human
  • BCL2 protein, human
  • BCL2L1 protein, human
  • BCL2L2 protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • PMAIP1 protein, human
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • bcl-X Protein