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Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer. Oncotarget 2014 Jun 30;5(12):4269-82 PMID: 24962213 PMCID: PMC4147322

Pubmed ID

24962213

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.

Author List

Qi X, Xie C, Hou S, Li G, Yin N, Dong L, Lepp A, Chesnik MA, Mirza SP, Szabo A, Tsai S, Basir Z, Wu S, Chen G

Authors

Guan Chen MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Aniko Szabo PhD Associate Professor in the Institute for Health and Equity department at Medical College of Wisconsin
Susan Tsai MD Associate Professor in the Surgery department at Medical College of Wisconsin




Scopus

2-s2.0-84905098265   9 Citations

MESH terms used to index this publication - Major topics in bold

Cell Line, Tumor
Cell Transformation, Neoplastic
Colonic Neoplasms
Humans
Phosphorylation
Signal Transduction
Transfection
ras Proteins
jenkins-FCD Prod-299 9ef562391eceb2b8f95265c767fbba1ce5a52fd6