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CHIP regulates AKT/FoxO/Bim signaling in MCF7 and MCF10A cells

Yanrong Lv1, Shanshan Song2, Kai Zhang1

  • 1Department of Breast Surgery, QiLu Hospital of Shandong University, Jinan, Shandong, China.

Plos One
|December 31, 2013
PubMed

Insights

Overexpression of C-terminus of Hsc70-interacting protein (CHIP) promotes cancer cell survival by disrupting the AKT/FoxO/Bim pathway, leading to apoptosis resistance. This mechanism involves regulating PTEN levels in breast cancer.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Apoptosis resistance is a hallmark of many human cancers, yet its underlying mechanisms are not fully understood.
  • The C-terminus of Hsc70-interacting protein (CHIP) has been implicated in various cellular processes, but its role in apoptosis resistance requires further elucidation.

Purpose of the Study:

  • To investigate the role of CHIP overexpression in inducing apoptosis resistance.
  • To elucidate the molecular mechanisms by which CHIP regulates apoptosis resistance, focusing on the AKT/FoxO/Bim signaling pathway.

Main Methods:

  • Utilized breast cancer (MCF7) and non-tumorigenic (MCF10A) cell lines to study CHIP overexpression.
  • Investigated the effects of CHIP on AKT, Forkhead box O (FoxO) transcription factors (FoxO1, FoxO3, FoxO4), Bim, and PTEN.
  • Employed PI3K inhibition to assess the critical signaling events in CHIP-induced apoptosis resistance.
  • Examined CHIP's role in regulating PTEN at both transcriptional and post-translational levels.
  • Corroborated findings in human breast cancer tissues.

Main Results:

  • CHIP overexpression activated AKT and inhibited FoxO transcription factors (FoxO1, FoxO3, FoxO4) in MCF7 and MCF10A cells.
  • CHIP overexpression led to the inhibition of Bim and PTEN transcription.
  • Inhibition of PI3K confirmed its critical role in CHIP-induced apoptosis resistance.
  • CHIP-mediated inhibition of FoxO3 resulted in decreased PTEN levels and further activation of the AKT survival pathway.
  • Findings were validated in clinical breast cancer samples.

Conclusions:

  • CHIP overexpression induces apoptosis resistance in breast cancer cells by modulating the AKT/FoxO/Bim signaling pathway.
  • CHIP regulates PTEN protein levels through both transcriptional and post-translational mechanisms, contributing to apoptosis resistance.
  • The CHIP-AKT/FoxO/Bim axis represents a potential therapeutic target for overcoming apoptosis resistance in cancer.

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