Dataset Information

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.

SUBMITTER: Wang H

PROVIDER: S-EPMC3138908 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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CCI-779 inhibits cell-cycle G2-M progression and invasion of castration-resistant prostate cancer via attenuation of UBE2C transcription and mRNA stability.

Wang Hongyan H Zhang Chunpeng C Rorick Anna A Wu Dayong D Chiu Ming M Thomas-Ahner Jennifer J Chen Zhong Z Chen Hongyan H Clinton Steven K SK Chan Kenneth K KK Wang Qianben Q

Cancer research 20110518 14

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 a ...[more]

PMID: 21593191

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Project description:The standard of care for head and neck cancer typically includes surgical resection of the tumor followed by targeted head and neck radiation. However depending on tumor location and stage, some cases may not require surgical resection while others may be treated with chemoradiation. Unfortunately, these radiation treatments cause chronic negative side effects for patients. These side effects are associated with damage to surrounding normal salivary gland tissue and include xerostomia, changes in taste and malnutrition. The underlying mechanisms of chronic radiation-induced salivary gland dysfunction are unknown, however, in rodent models persistently elevated proliferation is correlated with reduced stimulated salivary flow. The rapalogue, CCI-779, has been used in other cell systems to induce autophagy and reduce proliferation, therefore the aim of this study was to determine if CCI-779 could be utilized to ameliorate chronic radiation-induced salivary gland dysfunction. Four to six week old Atg5f/f; Aqp5-Cre, Atg5+/+; Aqp5-Cre and FVB mice were treated with targeted head and neck radiation. FVB mice were treated with CCI-779, chloroquine, or DMSO post-radiation. Stimulated salivary flow rates were determined and parotid and submandibular salivary gland tissues were collected for analyses. Mice with a defect in autophagy, via a conditional knockout of Atg5 in the salivary glands, display increased compensatory proliferation in the acinar cell compartment and hypertrophy at 24-72 hours following radiation. FVB mice treated with post-therapy CCI-779 have significant improvements in salivary gland physiology as determined by stimulated salivary flow rates, proliferation indices and amylase production and secretion. Consequently, post-radiation use of CCI-779 allows for improvement of salivary gland function and reestablishment of glandular homeostasis. As CCI-779 is already FDA approved for other uses, it could have a secondary use to alleviate the chronic side effects in head and neck cancer patients who have completed anti-tumor therapy.

Dataset Information

CCI-779 inhibits cell-cycle G2-M progression and invasion of castration-resistant prostate cancer via attenuation of UBE2C transcription and mRNA stability.

Publications

CCI-779 inhibits cell-cycle G2-M progression and invasion of castration-resistant prostate cancer via attenuation of UBE2C transcription and mRNA stability.

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