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K-Ras stabilization by estrogen via PKC? is involved in endometrial tumorigenesis.

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-?36 receptor. PKC? 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 PKC? knockdown. The role of PKC? in estrogen-induced tumorigenesis was confirmed in a mouse xenograft model by reduction of tumors after treatment with rottlerin, a PKC? inhibitor. Finally, levels of PKC? correlated with that of Ras in human endometrial tumor tissues. Stabilization of K-Ras by estrogen signaling involving PKC? up-regulation provides a potential therapeutic approach for treatment of endometrial cancer.

SUBMITTER: Koo KH

PROVIDER: S-EPMC4673268 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Koo Kyoung-Hwa KH Jeong Woo-Jeong WJ Cho Yong-Hee YH Park Jong-Chan JC Min Do Sik do S Choi Kang-Yell KY

Oncotarget 20150801 25

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 est ...[more]

PMID: 26015399

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