title: CCI-779 inhibits cell-cycle G2-M progression and invasion of castration-resistant prostate cancer via attenuation of UBE2C transcription and mRNA stability.
abstract: The cell-cycle G(2)-M phase gene UBE2C is overexpressed in various solid tumors including castration-resistant prostate cancer (CRPC). Our recent studies found UBE2C to be a CRPC-specific androgen receptor (AR) target gene that is necessary for CRPC growth, providing a potential novel target for therapeutic intervention. In this study, we showed that the G(1)-S cell-cycle inhibitor-779 (CCI-779), an mTOR inhibitor, inhibited UBE2C mRNA and protein expression in AR-positive CRPC cell models abl and C4-2B. Treatment with CCI-779 significantly decreased abl cell proliferation in vitro and in vivo through inhibition of cell-cycle progression of both G(2)-M and G(1)-S phases. In addition, exposure of abl and C4-2B cells to CCI-779 also decreased UBE2C-dependent cell invasion. The molecular mechanisms for CCI-779 inhibition of UBE2C gene expression involved a decreased binding of AR coactivators SRC1, SRC3, p300, and MED1 to the UBE2C enhancers, leading to a reduction in RNA polymerase II loading to the UBE2C promoter, and attenuation of UBE2C mRNA stability. Our data suggest that, in addition to its ability to block cell-cycle G(1) to S-phase transition, CCI-779 causes a cell-cycle G(2)-M accumulation and an inhibition of cell invasion through a novel UBE2C-dependent mechanism, which contributes to antitumor activities of CCI-779 in UBE2C overexpressed AR-positive CRPC.
authors: Division of Pharmaceutical Sciences, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors: Hongyan
authors: H
authors: Wang
authors: Chunpeng
authors: C
authors: Zhang
authors: Anna
authors: A
authors: Rorick
authors: Dayong
authors: D
authors: Wu
authors: Ming
authors: M
authors: Chiu
authors: Jennifer
authors: J
authors: Thomas-Ahner
authors: Zhong
authors: Z
authors: Chen
authors: Hongyan
authors: H
authors: Chen
authors: Steven K
authors: SK
authors: Clinton
authors: Kenneth K
authors: KK
authors: Chan
authors: Qianben
authors: Q
authors: Wang
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