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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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Resistance to BH3 mimetic S1 in SCLC cells that up-regulate and phosphorylate Bcl-2 through ERK1/2

Yubo Liu1, Zhichao Zhang, Ting Song

  • 1State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China.

British Journal of Pharmacology
|May 9, 2013
PubMed
Abstract

Insights

Small-cell lung cancer (SCLC) resistance to BH3 mimetics involves increased Bcl-2 and phosphorylated Bcl-2 (pBcl-2) levels. The MAPK/ERK pathway drives this resistance by upregulating Bcl-2 and promoting pBcl-2, impacting cell survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Research

Background:

  • Bcl-2 is overexpressed in small-cell lung cancer (SCLC), promoting survival and therapeutic resistance.
  • Understanding resistance mechanisms to BH3 mimetics is crucial for SCLC treatment.

Purpose of the Study:

  • To identify factors determining SCLC sensitivity to the BH3 mimetic S1.
  • To elucidate the mechanisms of resistance to BH3 mimetics in SCLC.

Main Methods:

  • Western blot analysis of Bcl-2 family members.
  • Derivation of acquired resistant SCLC cell lines.
  • Quantitative PCR and gene silencing for Bcl-2 investigation.

Main Results:

  • Increased Bcl-2 and phosphorylated Bcl-2 (pBcl-2) correlated with SCLC resistance.
  • BH3 mimetics induced endoplasmic reticulum (ER) stress and activated the MAPK/ERK pathway.
  • ERK1/2 activation led to Bcl-2 upregulation and sustained phosphorylation, contributing to resistance.

Conclusions:

  • Novel insights into ER stress and apoptotic pathway crosstalk in SCLC.
  • pBcl-2 plays a critical role in BH3 mimetic resistance via protein sequestration and feedback loops.
  • Findings advance understanding of therapeutic resistance in SCLC.
Keywords:
BH3 mimeticsBcl-2 phosphorylationERK1/2SCLC

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