K-Ras stabilization by estrogen via PKCδ is involved in endometrial tumorigenesis

Kyoung-Hwa Koo; Woo-Jeong Jeong; Yong-Hee Cho; Jong-Chan Park; Do Sik Min; Kang-Yell Choi

doi:10.18632/oncotarget.4049

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Research Papers:

K-Ras stabilization by estrogen via PKCδ is involved in endometrial tumorigenesis

Kyoung-Hwa Koo, Woo-Jeong Jeong, Yong-Hee Cho, Jong-Chan Park, Do Sik Min and Kang-Yell Choi _

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Oncotarget. 2015; 6:21328-21340. https://doi.org/10.18632/oncotarget.4049

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Abstract

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

Correspondence to:

Kang-Yell Choi, email:

Keywords: endometrial cancer, estrogen, tumorigenesis, K-Ras, PKCδ

Received: February 27, 2015 Accepted: April 30, 2015 Published: May 08, 2015

Abstract

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.

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Research Papers:

K-Ras stabilization by estrogen via PKCδ is involved in endometrial tumorigenesis

Abstract