Abstract 574: 1,4-phenylenebis(methylene)selenocyanate (p-XSC) inhibits mammalian target of rapamycin complex 2 (mTORC2) signaling in prostate cancer cells

Abstract

Abstract The lack of treatment for worried-well patients with high-grade prostatic intraepithelial neoplasia combined with issues of recurrence and hormone resistance in prostate cancer survivors remains a major public health obstacle. The long latency of prostate cancer development provides an opportunity to intervene with mechanistically-based agents at various stages of disease progression. Preclinical studies and immunohistochemical analyses of human prostate adenocarcinoma tissues have implicated the mammalian target of rapamycin (mTOR) signaling pathway in the progression of prostate cancer and its transition to androgen independence, suggesting mTOR as a potential target for new therapies. Preclinical studies in human prostate cancer cells also show that there is cross-talk between mTOR and androgen receptor signaling, a process critical for prostate cancer growth and survival. We have previously shown that the synthetic organoselenium compound p-XSC effectively inhibits cell viability and down-regulates androgen receptor expression and transcriptional activity in androgen responsive (AR) and androgen independent (AI) human prostate cancer cells; the naturally occurring selenomethionine was either ineffective or weakly active at non-physiological levels. Therefore, we focused our study on the effects of p-XSC and we hypothesized that it inhibits prostate cancer cell growth by interfering with mTOR signaling and that inhibition of this pathway may be linked to down-regulation of androgen receptor signaling in these cells. Here we show that p-XSC inhibits phosphorylation of mTOR in both AR LNCaP and AI LNCaP C4-2 human prostate cancer cells. This inhibition is attenuated by stimulation with androgens in AR LNCaP but not AI C4-2 cells, emphasizing a cross-talk between the two pathways. p-XSC also decreases mTOR binding to mTOR complex 2 (mTORC2) protein Rictor in AR LNCaP and AI C4-2 cells and inhibits the phosphorylation of mTORC2 downstream target Akt. Since p-XSC appears to be inhibiting mTORC2 as well as androgen signaling, we further hypothesized that the combination of p-XSC with rapamycin, which primarily targets mTORC1, may be a superior approach to inhibit prostate cancer cell growth than either agent alone. Our data clearly support this hypothesis. Validation of mTOR as a target of selenium in prostate cancer will provide evidence for its potential role against advanced and hormone refractory prostate disease either individually or in combination with therapies that target other signaling pathways. Support: NIH CA111842, DOD W81XWH-08-1-0297 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 574.