Oncotarget

Research Papers:

JQ1 suppresses tumor growth via PTEN/PI3K/AKT pathway in endometrial cancer

Haifeng Qiu, Jing Li, Leslie H. Clark, Amanda L. Jackson, Lu Zhang, Hui Guo, Joshua E. Kilgore, Paola A. Gehrig, Chunxiao Zhou and Victoria L. Bae-Jump _

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Oncotarget. 2016; 7:66809-66821. https://doi.org/10.18632/oncotarget.11631

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Abstract

Haifeng Qiu1,2, Jing Li3, Leslie H. Clark2, Amanda L. Jackson2, Lu Zhang2,4, Hui Guo2,4, Joshua E. Kilgore2, Paola A. Gehrig2, Chunxiao Zhou2,5, Victoria L. Bae-Jump2,5

1Department of Obstetrics and Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

2Division of Gynecological Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

3Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

4Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan, China

5Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Correspondence to:

Victoria L. Bae-Jump, email: vbae@unch.unc.edu

Chunxiao Zhou, email: czhou@med.unc.edu

Keywords: endometrial cancer, JQ1, BRD4 inhibitor, PTEN/PI3K/AKT signal pathway, intrinsic resistance

Received: April 15, 2016     Accepted: August 10, 2016     Published: August 26, 2016

ABSTRACT

Overexpression of c-Myc is associated with worse outcomes in endometrial cancer, indicating that c-Myc may be a promising target for endometrial cancer therapy. A novel small molecule, JQ1, has been shown to block BRD4 resulting in inhibition of c-Myc expression and tumor growth. Thus, we investigated whether JQ1 can inhibit endometrial cancer growth in cell culture and xenograft models. In PTEN-positive endometrial cancer cells, JQ1 significantly suppressed cell proliferation via induction of G1 phase arrest and apoptosis in a dose-dependent manner, accompanied by a sharp decline in cyclin D1 and CDK4 protein expression. However, PTEN-negative endometrial cancer cells exhibited intrinsic resistance to JQ1, despite significant c-Myc inhibition. Moreover, we found that PTEN and its downstream PI3K/AKT signaling targets were modulated by JQ1, as evidenced by microarray analysis. Silencing of PTEN in PTEN-positive endometrial cancer cells resulted in resistance to JQ1, while upregulation of PTEN in PTEN-negative endometrial cancer cells increased sensitivity to JQ1. In xenografts models of PTEN-positive and PTEN-knock-in endometrial cancer, JQ1 significantly upregulated the expression of PTEN, blocked the PI3K/AKT signaling pathway and suppressed tumor growth. These effects were attenuated in PTEN-negative and PTEN-knockdown xenograft models. Thus, JQ1 resistance appears to be highly associated with the status of PTEN expression in endometrial cancer. Our findings suggest that targeting BRD4 using JQ1 might serve as a novel therapeutic strategy in PTEN-positive endometrial cancers.


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