Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer

Xiaomei Qi, Congying Xie, Songwang Hou, Gang Li, Ning Yin, Lei Dong, Adrienne Lepp, Marla A. Chesnik, Shama P. Mirza, Aniko Szabo, Susan Tsai, Zainab Basir, Shixiu Wu, Guan Chen

Research output: Contribution to journalArticlepeer-review

Abstract

A cancer phenotype is driven by several proteins and targeting a cluster of functionally interdependent molecules should be more effective for therapeutic intervention. This is specifically important for Ras-dependent cancer, as mutated (MT) Ras is non-druggable and targeting its interaction with effectors may be essential for therapeutic intervention. Here, we report that a protein-complex activated by the Ras effector p38γ MAPK is a novel therapeutic target for K-Ras-dependent colon cancer. Unbiased proteomic screening and immune-precipitation analyses identified p38γ interaction with heat shock protein 90 (Hsp90) and K-Ras in K-Ras MT, but not wild-type (WT), colon cancer cells, indicating a role of this complex in Ras-dependent growth. Further experiments showed that this complex requires p38γ and Hsp90 activity to maintain MT, but not WT, K-Ras protein expression. Additional studies demonstrated that this complex is activated by p38γ-induced Hsp90 phosphorylation at S595, which is important for MT K-Ras stability and for K-Ras dependent growth. Of most important, pharmacologically inhibition of Hsp90 or p38γ activity disrupts the complex, decreases K-Ras expression, and selectively inhibits the growth of K-Ras MT colon cancer in vitro and in vivo. These results demonstrated that the p38γ-activated ternary complex is a novel therapeutic target for K-Ras-dependent colon cancer.

Original languageEnglish (US)
Pages (from-to)4269-4282
Number of pages14
JournalOncotarget
Volume5
Issue number12
DOIs
StatePublished - 2014

Keywords

  • Colon cancer
  • Hsp90
  • K-Ras
  • Ternary complex
  • Therapeutic target
  • p38γ MAPK

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer'. Together they form a unique fingerprint.

Cite this