Research Papers:

Cross-talk between p21-activated kinase 4 and ERα signaling triggers endometrial cancer cell proliferation

Tao Su, Jun-Jie Qu, Kai Wang, Bi-Lan Li, Dong Zhao, Yi-Ping Zhu, Lei Ye, Wen Lu _ and Xiao-Ping Wan

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Oncotarget. 2017; 8:68083-68094. https://doi.org/10.18632/oncotarget.19188

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Tao Su1,2, Jun-Jie Qu1, Kai Wang3, Bi-Lan Li1, Dong Zhao1, Yi-Ping Zhu1, Lei Ye1, Wen Lu1 and Xiao-Ping Wan1

1Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, P.R. China

2Department of Gynecology, The International Peace Maternity & Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China

3Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, P.R. China

Correspondence to:

Wen Lu, email: [email protected]

Xiao-Ping Wan, email: [email protected]

Keywords: endometrial carcinoma, p21-activated kinase 4 (Pak4), estrogen receptor alpha (ERα), cross-talk, proliferation

Received: July 16, 2016     Accepted: June 13, 2017     Published: July 12, 2017


Cross-talk between estrogen receptor alpha (ERα) and signal transduction pathways plays an important role in the progression of endometrial cancer (EC). Here, we show that 17β-estradiol (E2) stimulation increases p21-activated kinase 4 (Pak4) expression and activation in ER-positive EC cells. The estrogen-induced Pak4 activation is mediated via the PI3K/AKT pathway. Estrogen increases Pak4 and phosphorylated-Pak4 (p-Pak4) nuclear accumulation, and Pak4 in turn enhances ERα trans-activation. Depletion or functional inhibition of Pak4 abrogates EC cell proliferation induced by E2, whereas overexpression of Pak4 rescues cell proliferation decreased by inhibiting the estrogen pathway. Pak4 knockdown decreases cyclin D1 expression and induces G1-S arrest. Importantly, Pak4 suppression inhibits E2 induced EC tumor growth in vivo, in a mouse xenograft model. These data demonstrate that estrogen stimulation increases Pak4 expression and activation, which in turn enhances ERα transcriptional activity and ERα-dependent gene expression, resulting in increased proliferation of EC cells. Thus inhibition of Pak4-ERα signaling may represent a novel therapeutic strategy against endometrial carcinoma.

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