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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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-a36 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.

Original languageEnglish
Pages (from-to)21328-21340
Number of pages13
JournalOncotarget
Volume6
Issue number25
DOIs
Publication statusPublished - 2015

All Science Journal Classification (ASJC) codes

  • Oncology

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