title: JQ1 suppresses tumor growth via PTEN/PI3K/AKT pathway in endometrial cancer.
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.
authors: Department of Obstetrics and Gynecology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.|Division of Gynecological Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Haifeng
authors: H
authors: Qiu
authors: Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors: Jing
authors: J
authors: Li
authors: Division of Gynecological Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Leslie H
authors: LH
authors: Clark
authors: Division of Gynecological Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Amanda L
authors: AL
authors: Jackson
authors: Division of Gynecological Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan, China.
authors: Lu
authors: L
authors: Zhang
authors: Division of Gynecological Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Jinan, China.
authors: Hui
authors: H
authors: Guo
authors: Division of Gynecological Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Joshua E
authors: JE
authors: Kilgore
authors: Division of Gynecological Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Paola A
authors: PA
authors: Gehrig
authors: Division of Gynecological Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Chunxiao
authors: C
authors: Zhou
authors: Division of Gynecological Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Victoria L
authors: VL
authors: Bae-Jump
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001381:Azepines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014230:Triazoles / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D014230:Triazoles; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: BRD4 inhibitor; JQ1; PTEN/PI3K/AKT signal pathway; endometrial cancer; intrinsic resistance