Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer
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Xiaomei Qi1,*, Congying Xie2,*, Songwang Hou1, Gang Li2, Ning Yin1, Lei Dong2, Adrienne Lepp1, Marla A. Chesnik3, Shama P. Mirza3, Aniko Szabo4, Susan Tsai5, Zainab Basir6, Shixiu Wu2,8 and Guan Chen1,7
1 Department of Pharmacology and Toxicology, Medical College of Wisconsin
2 Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical College, Wenzhou, China
3 Department of Biochemistry, Biotechnology & Bioengineering Center, Medical College of Wisconsin, Milwaukee, WI
4 Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI
5 Department of Surgery, Medical College of Wisconsin, Milwaukee, WI
6 Department of Pathology, Medical College of Wisconsin, Milwaukee, WI
7 Research Services, Zablocki Veterans Affairs Medical Center, Medical College of Wisconsin, Milwaukee, WI
8 The current address at Cancer Center, Hangzhou Cancer Hospital, Zhejiang, China
* These authors contributed equally to work
Guan Chen, email:
Shixiu Wu, email:
Keywords: p38γ MAPK, Hsp90, K-Ras, ternary complex, therapeutic target, and colon cancer
Received: February 20, 2014 Accepted: May 23, 2014 Published: May 25, 2014
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.
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