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PI3K/AKT/mTOR pathway promotes progestin resistance in endometrial cancer cells by inhibition of autophagy

Authors Liu H, Zhang L, Zhang X, Cui Z

Received 27 August 2015

Accepted for publication 5 February 2016

Published 6 June 2017 Volume 2017:10 Pages 2865—2871

DOI https://doi.org/10.2147/OTT.S95267

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Ram Prasad

Peer reviewer comments 4

Editor who approved publication: Dr Jianmin Xu

Hua Liu,1,2 Liqin Zhang,2 Xuyan Zhang,2 Zhumei Cui1

1Department of Gynecology, Affiliated Hospital of Qingdao Medical College, Qingdao University, Qingdao, 2Department of Gynecology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, People’s Republic of China

Abstract: Endometrial cancer (EC) is now one of the most common malignant tumors in young women. In all, 90% of young patients with EC have a high expression of progesterone recep­tor, can be treated with progestin, and have very good prognosis. However, some of the young EC patients are resistant to progestin, the mechanism of which is unclear. To illuminate the mechanism by which endometrial cells acquire progestin resistance, we treated Ishikawa cells by slowly increasing dosage of progestin and established a progestin-resistant cell subline. We show here that progesterone resistant cells acquire increased proliferation rate and interestingly decreased autophagy. To uncover the mechanism by which cells increase proliferation and bypass autophagy, we found higher activation of phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway was necessary to this malignant acquirement by RNAi technique. Further, we elucidated that activation of mTOR was sufficient and necessary for progestin resistance. RAD001, an inhibitor of mTOR, decreased phosphorylation of mTOR and inhibited proliferation of progestin-resistant cancer cells by promoting autophagy. Thus, our results indicated that mTOR can be a target to treat the progestin-resistant EC.

Keywords: progesterone receptor, RAD001, proliferation, Ishikawa, phosphorylation
 

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