title: 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: Department of Pharmacology and Toxicology, Medical College of Wisconsin.
authors: Xiaomei
authors: X
authors: Qi
authors: Congying
authors: C
authors: Xie
authors: Songwang
authors: S
authors: Hou
authors: Gang
authors: G
authors: Li
authors: Ning
authors: N
authors: Yin
authors: Lei
authors: L
authors: Dong
authors: Adrienne
authors: A
authors: Lepp
authors: Marla A
authors: MA
authors: Chesnik
authors: Shama P
authors: SP
authors: Mirza
authors: Aniko
authors: A
authors: Szabo
authors: Susan
authors: S
authors: Tsai
authors: Zainab
authors: Z
authors: Basir
authors: Department of Radiation Oncology, First Affiliated Hospital, Wenzhou Medical College, Wenzhou, China.
authors: Shixiu
authors: S
authors: Wu
authors: Department of Pharmacology and Toxicology, Medical College of Wisconsin; Research Services, Zablocki Veterans Affairs Medical Center, Medical College of Wisconsin, Milwaukee, WI.
authors: Guan
authors: G
authors: Chen
mesh_terms: D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics*; D006801:Humans; D010766:Phosphorylation; D015398:Signal Transduction; D014162:Transfection; D018631:ras Proteins / Q000235:genetics*
chemical_list: D018631:ras Proteins