Abstract 2584: Notch1 and Notch2 activation by phenethyl isothiocyanate hinders its inhibitory effect on prostate cancer cell migration

Abstract

Abstract Practical and safe modalities for chemoprevention of prostate cancer are clinically attractive because of high mortality associated with this malignancy in American men. Plant products, including constituents of fruits and vegetables, continue to attract attention for the discovery of novel cancer chemopreventive agents. Phenethyl isothiocyanate (PEITC) is one such promising cancer chemopreventive agent abundant in edible cruciferous vegetables such as watercress. Evidence for protective effect of cruciferous vegetables and their components, including PEITC, against prostate cancer derives from population-based observational studies as well as laboratory investigations. For example, we have shown previously that PEITC administration in the diet (3 µmol/g diet) significantly inhibits incidence as well as burden of poorly-differentiated prostate cancer in the dorsolateral prostate of Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) transgenic mice. Cancer chemopreventive response to PEITC is attributed to its ability to inhibit multiple oncogenic signaling pathways, including nuclear factor-βB, Akt, and androgen receptor. The present study demonstrates, for the first time, that PEITC treatment activates Notch1 and Notch2 in malignant as well as normal human prostate cells. The Notch1 and Notch2 belong to a family of transmembrane receptors implicated in prostate cancer development and metastasis. Exposure of human prostate cancer cells (LNCaP, PC-3, and DU145) and a normal human prostate epithelial cell line (PrEC) to PEITC resulted in cleavage (active form) of Notch1 and Notch2, which was associated with an increase in transcriptional activity of Notch. PEITC treatment caused induction of Notch ligands Jagged1 and Jagged2, overexpression of γ-secretase complex components Presenilin1 and Nicastrin, nuclear enrichment of cleaved Notch2, and/or up-regulation of Notch1, Notch2, Jagged1, and/or Jagged2 mRNA in cancer cells. PEITC-induced apoptosis in LNCaP and PC-3 cells was significantly attenuated by RNA interference of Notch2, but not by pharmacological inhibition of Notch1. Inhibition of PC-3 and LNCaP cell migration resulting from PEITC exposure was significantly augmented by RNA interference of Notch2 as well as pharmacological inhibition of Notch1 activation. Nuclear expression of cleaved Notch2 protein was significantly higher in PC-3 xenografts from PEITC-treated athymic mice and dorsolateral prostates from PEITC-fed TRAMP mice compared with the respective control. Because Notch signaling is implicated in epithelial-mesenchymal transition and metastasis, the present study suggests that anti-metastatic effect of PEITC may be augmented by a combination regimen involving PEITC and a Notch inhibitor. This investigation was supported by the US PHS grant RO1 CA101753-08. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2584. doi:1538-7445.AM2012-2584