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Heterogeneous nuclear ribonucleoprotein H blocks MST2-mediated apoptosis in cancer cells by regulating A-Raf

Jens Rauch1, Eric O'Neill, Brigitte Mack

  • 1Department of Head and Neck Research, Ludwig-Maximilians-Universität München, D-81377 Munich, Germany.

Cancer Research
|February 11, 2010
PubMed

Insights

A-Raf kinase prevents cancer cell death by inactivating MST2 kinase, a process dependent on the hnRNP H splice factor. This mechanism helps tumor cells evade apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • A-Raf is an oncogenic kinase in the MAP/ERK signaling pathway.
  • A-Raf's low MEK kinase activity suggests alternative functions.
  • Cancer cells often evade apoptosis to promote tumor growth.

Purpose of the Study:

  • To investigate the non-canonical functions of A-Raf in cancer.
  • To elucidate the role of A-Raf in preventing cancer cell apoptosis.
  • To identify factors regulating A-Raf's anti-apoptotic function.

Main Methods:

  • Small interfering RNA (siRNA) mediated knockdown of hnRNP H and A-Raf.
  • Analysis of apoptosis in cancer cells.
  • Assessment of MST2 kinase activity and localization.
  • In vivo expression studies in colon cancer specimens.

Main Results:

  • A-Raf prevents apoptosis by sequestering and inactivating proapoptotic MST2 kinase.
  • hnRNP H expression is required for A-Raf's anti-apoptotic function.
  • Knockdown of hnRNP H or A-Raf leads to MST2-dependent apoptosis.
  • Overexpression of hnRNP H and A-Raf correlates with colon cancer tissues.
  • Enforced expression of hnRNP H or A-Raf counteracted etoposide-induced apoptosis.

Conclusions:

  • A-Raf, in conjunction with hnRNP H, provides a novel mechanism for cancer cells to escape apoptosis.
  • The A-Raf/hnRNP H/MST2 axis represents a potential therapeutic target in cancer treatment.
  • Tumor cells hijack this pathway to promote survival and proliferation.

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