Abstract 5563: Dietary phenethyl isothiocyanate administration inhibits prostate cancer development in transgenic adenocarcinoma of mouse prostate mice in association with induction of autophagy and suppression of plasma clusterin

Abstract

Abstract We have shown previously that phenethyl isothiocyanate (PEITC), a constituent of edible cruciferous vegetables (e.g., watercress), suppresses growth of cultured and xenografted human prostate cancer cells in association with apoptotic and autophagic cell death. The goals of the present study were to: (a) determine effect of dietary administration of PEITC on prostate cancer development using a transgenic mouse model (Transgenic Adenocarcinoma of Mouse Prostate; TRAMP); (b) elucidate whether PEITC utilizes the same mechanisms in vivo as it does in cultured prostate cancer cells; and (c) identify biomarker(s) predictive of PEITC response for future clinical applications. Administration of PEITC in the diet (3 μmol PEITC/g diet for 19 weeks) significantly inhibited burden (affected area) of poorly-differentiated cancer in the dorsolateral prostate (DLP) of TRAMP mice without causing weight loss or any other side effects. PEITC was detectable in plasma (∼1451 nM) as well as in the prostate (∼1138 nmol/kg) of non-transgenic littermates placed on PEITC-supplemented diet. The PEITC-mediated inhibition of prostate cancer progression correlated with a decrease in the expression of cell proliferation marker Ki-67. To our surprise, number of apoptotic bodies was comparable in the DLP of Control and PEITC-fed mice. On the other hand, the DLP from mice placed on PEITC-supplemented diet exhibited 2-3 fold increase in number of autophagosomes (judged by transmission electron microscopy) and elevated expression of autophagy regulator microtubule-associated protein 1 light chain 3 (judged by immunohistochemistry), as compared with that of Control group. Consistent with these observations, level of selective autophagy substrate p62 (also known as sequestosome 1) was reduced in the DLP of PEITC-fed mice in comparison with Control. The PEITC-mediated inhibition of prostate cancer development was accompanied by a marked increase in expression of E-cadherin. Additionally, 2-dimensional gel electrophoresis coupled with mass spectrometry revealed a marked decrease in plasma clusterin in PEITC-treated mice compared with Controls. Together these results indicate that PEITC administration inhibits prostate cancer progression in TRAMP mice in association with reduced cell proliferation and induction of autophagy. Furthermore, the present study discovers plasma clusterin as a potential biomarker of PEITC response. This investigation was supported by the USPHS grant 2 RO1 CA101753-07, awarded by the National Cancer Institute. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5563. doi:10.1158/1538-7445.AM2011-5563