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

• Published in: Oncotarget Vol. 5; no. 12; pp. 4269 - 4282
• Main Authors: Qi, Xiaomei, Xie, Congying, Hou, Songwang, Li, Gang, Yin, Ning, Dong, Lei, Lepp, Adrienne, Chesnik, Marla A, Mirza, Shama P, Szabo, Aniko, Tsai, Susan, Basir, Zainab, Wu, Shixiu, Chen, Guan
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 30.06.2014
• Subjects: Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Colonic Neoplasms - genetics; Humans; Phosphorylation; ras Proteins - genetics; Research Paper; Signal Transduction; Transfection
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.2001

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.