K-Ras stabilization by estrogen via PKCδ is involved in endometrial tumorigenesis
Metrics: PDF 1419 views | HTML 2122 views | ?
Kyoung-Hwa Koo1,2, Woo-Jeong Jeong1,2, Yong-Hee Cho1,2, Jong-Chan Park1,2, Do Sik Min1,3 and Kang-Yell Choi1,2
1 Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea
2 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
3 Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, Korea
Kang-Yell Choi, email:
Keywords: endometrial cancer, estrogen, tumorigenesis, K-Ras, PKCδ
Received: February 27, 2015 Accepted: April 30, 2015 Published: May 08, 2015
Estrogens are considered as a major risk factor of endometrial cancer. In this study, we identified a mechanism of tumorigenesis in which K-Ras protein is stabilized via estrogen signaling through the ER-α36 receptor. PKCδ was shown to stabilize K-Ras specifically via estrogen signaling. Estrogens stabilize K-Ras via inhibition of polyubiquitylation-dependent proteasomal degradation. Estrogen-induced cellular transformation was abolished by either K-Ras or PKCδ knockdown. The role of PKCδ in estrogen-induced tumorigenesis was confirmed in a mouse xenograft model by reduction of tumors after treatment with rottlerin, a PKCδ inhibitor. Finally, levels of PKCδ correlated with that of Ras in human endometrial tumor tissues. Stabilization of K-Ras by estrogen signaling involving PKCδ up-regulation provides a potential therapeutic approach for treatment of endometrial cancer.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.