Polo-like kinase 1 (Plk1), a crucial regulator of cell cycle progression, is overexpressed in multiple types of cancers, and has been proven to be a potent and promising target for cancer treatment. In case of prostate cancer, we once showed that anti-neoplastic activity of Plk1 inhibitor is largely due to inhibition of androgen receptor (AR) signaling. However, we also discovered that Plk1 inhibition causes activation of the β-catenin pathway and increased ex-pression of c-Myc, eventually resulting in resistance to Plk1 inhibition. JQ1, a selective small molecule inhibitor targeting the amino-terminal bromodomains of BRD4, has been shown to dramatically inhibit c-Myc expression and AR signaling, exhibiting anti-proliferative effects in a range of cancers. Since c-Myc and AR signaling are essential for prostate cancer initiation and progression, we aim to test whether targeting Plk1 and BRD4 at the same time is an effective approach to treat prostate cancer. Herein, we show that a combination of Plk1 inhibitor GSK461364A and BRD4 inhibitor JQ1 had a strong synergis-tic effect on castration-resistant prostate cancer (CRPC) cell lines, as well as in CRPC xeno-graft tumors. Mechanistically, the synergistic effect is likely due to two reasons: 1) Plk1 in-hibition results in the accumulation of β-catenin in the nucleus, thus elevation of c-Myc ex-pression, whereas JQ1 treatment directly suppresses c-Myc transcription. 2) Plk1 and BRD4 dual inhibition acts synergistically in inhibition of AR signaling.
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