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

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.

• Authors: 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
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 12 Pg. 4269-82 (Jun 30 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24962213 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• ras Proteins

Topics

• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics)
• Colonic Neoplasms (genetics)
• Humans
• Phosphorylation
• Signal Transduction
• Transfection
• ras Proteins (genetics)