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Non-Invasive Ultrasound Assessment of Endometrial Cancer Progression in Pax8-Directed Deletion of the Tumor Suppressors Arid1a and Pten in Mice
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JQ1 suppresses tumor growth via PTEN/PI3K/AKT pathway in endometrial cancer

Haifeng Qiu, Jing Li, Leslie H Clark

    Oncotarget
    |August 31, 2016
    PubMed

    Insights

    The small molecule JQ1 inhibits endometrial cancer growth by targeting BRD4, but its effectiveness depends on PTEN expression. PTEN-positive cancers show sensitivity, while PTEN-negative cancers develop resistance.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Cancer Therapeutics

    Background:

    • Overexpression of c-Myc correlates with poor outcomes in endometrial cancer, identifying it as a therapeutic target.
    • JQ1, a novel small molecule, inhibits c-Myc expression and tumor growth by blocking BRD4.

    Purpose of the Study:

    • To investigate the efficacy of JQ1 in inhibiting endometrial cancer growth using cell culture and xenograft models.
    • To determine the role of PTEN (Phosphatase and tensin homolog) in mediating JQ1 sensitivity or resistance in endometrial cancer.

    Main Methods:

    • Cell proliferation assays, cell cycle analysis, apoptosis assays, and Western blotting were performed on PTEN-positive and PTEN-negative endometrial cancer cell lines treated with JQ1.
    • Microarray analysis was used to identify signaling pathways modulated by JQ1.
    • Xenograft models of endometrial cancer were utilized to assess JQ1's in vivo effects on tumor growth and PTEN/PI3K/AKT signaling.

    Main Results:

    • JQ1 suppressed proliferation and induced G1 arrest and apoptosis in PTEN-positive cells, decreasing cyclin D1 and CDK4 expression.
    • PTEN-negative cells exhibited resistance to JQ1 despite c-Myc inhibition.
    • JQ1 modulated PTEN and PI3K/AKT signaling; PTEN silencing caused JQ1 resistance, while PTEN upregulation increased sensitivity.
    • In vivo, JQ1 upregulated PTEN, inhibited PI3K/AKT signaling, and suppressed tumor growth in PTEN-positive xenografts, with attenuated effects in PTEN-negative models.

    Conclusions:

    • JQ1 resistance in endometrial cancer is strongly associated with PTEN expression status.
    • Targeting BRD4 with JQ1 represents a potential therapeutic strategy for PTEN-positive endometrial cancers.
    Keywords:
    BRD4 inhibitorJQ1PTEN/PI3K/AKT signal pathwayendometrial cancerintrinsic resistance

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