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BEX1 promotes imatinib-induced apoptosis by binding to and antagonizing BCL-2

Qian Xiao1, Yeting Hu1, Yue Liu1

  • 1The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Plos One
|March 15, 2014
PubMed

Insights

Brain expressed X-linked 1 (BEX1) interacts with B-cell lymphoma 2 (BCL-2) to promote apoptosis and overcome imatinib resistance in cancer cells. This BEX1/BCL-2 pathway offers a novel mechanism for treating resistant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Tumor cells develop imatinib resistance through enhanced anti-apoptotic mechanisms, often independent of the breakpoint cluster region/Abelson tyrosine kinase gene (BCR/ABL).
  • Brain expressed X-linked 1 (BEX1) is silenced in imatinib-resistant cells, and its re-expression restores sensitivity and induces apoptosis.
  • The precise mechanism by which BEX1 exerts its pro-apoptotic function in imatinib resistance remains unclear.

Purpose of the Study:

  • To elucidate the mechanism underlying BEX1's pro-apoptotic function in the context of imatinib resistance.
  • To identify proteins interacting with BEX1 and investigate their role in BEX1-mediated apoptosis.
  • To explore the potential of the BEX1/BCL-2 pathway as a therapeutic target for overcoming imatinib resistance.

Main Methods:

  • Yeast two-hybrid screening to identify BEX1-interacting proteins.
  • Co-immunoprecipitation assays to confirm the interaction between BEX1 and B-cell lymphoma 2 (BCL-2).
  • Subcellular localization studies (mitochondria) and analysis of specific BEX1 regions (33K-64Q) for interaction and apoptotic function.
  • Assessment of BCL-2/BCL-2-associated X protein (BAX) heterodimer formation.

Main Results:

  • B-cell lymphoma 2 (BCL-2) was identified as a BEX1-interacting protein, with the interaction confirmed by co-immunoprecipitation.
  • BEX1, similar to BCL-2, localizes to the mitochondria, and a specific region (33K-64Q) is crucial for this localization and BCL-2 interaction.
  • The BEX1/BCL-2 interaction suppresses the formation of anti-apoptotic BCL-2/BCL-2-associated X protein (BAX) heterodimers, thereby promoting imatinib-induced apoptosis.

Conclusions:

  • A novel interaction between BEX1 and BCL-2 has been discovered.
  • This interaction facilitates imatinib-induced apoptosis by modulating BCL-2/BAX heterodimerization.
  • The BEX1/BCL-2 pathway represents a new mechanism contributing to imatinib resistance and a potential therapeutic target.

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