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c-Src-p38 mitogen-activated protein kinase signaling is required for Akt activation in response to ionizing radiation

Min-Jung Kim1, Joo-Yun Byun, Chang-Hwan Yun

  • 1Laboratory of Molecular Biochemistry, Department of Chemistry, Hanyang University, 17 Haengdang-Dong, Seongdong-Gu, Seoul, Korea.

Molecular Cancer Research : MCR
|December 17, 2008
PubMed

Insights

The c-Src-Rac1-p38 MAPK pathway activates Akt, promoting cancer cell survival against radiation. Inhibiting p38 MAPK increases radiation sensitivity by blocking Akt phosphorylation, revealing a key mechanism in radiation resistance.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Cancer Research

Background:

  • The Akt and MAPK pathways are crucial for tumor cell survival and radiation resistance.
  • The precise molecular link between MAPK and Akt in radiation-induced cell survival remains unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which MAPK signaling influences Akt activation and cell survival in response to ionizing radiation.
  • To investigate the role of the c-Src-Rac1-p38 MAPK pathway in Akt activation and radiation resistance.

Main Methods:

  • Investigated Akt and MAPK pathway activation following ionizing radiation exposure in human cancer cells.
  • Utilized specific inhibitors for c-Jun NH(2)-terminal kinase and p38 MAPK.
  • Employed dominant-negative Rac1 (RacN17) and c-Src inhibition to assess pathway involvement.
  • Monitored phosphorylation of Akt at Thr(308) and Ser(473) and activation of p38 MAPK and Rac1.

Main Results:

  • Ionizing radiation activated Akt (Thr(308) and Ser(473) phosphorylation) and MAPK pathways (p38 and c-Jun NH(2)-terminal kinase).
  • Inhibition of p38 MAPK enhanced radiation sensitivity and specifically abolished radiation-induced Akt Ser(473) phosphorylation.
  • The c-Src-Rac1-p38 MAPK pathway was identified as essential for radiation-induced Akt activation and subsequent cell survival.

Conclusions:

  • The c-Src-Rac1-p38 MAPK pathway is critical for Akt activation in response to ionizing radiation.
  • This pathway plays a significant cytoprotective role in human cancer cells, contributing to radiation resistance.

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