Oncotarget

Research Papers:

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 and Guan Chen _

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Oncotarget. 2014; 5:4269-4282. https://doi.org/10.18632/oncotarget.2001

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Abstract

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

Correspondence:

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

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.


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