Abstract
Phenethyl isothiocyanate (PEITC) is a promising cancer chemopreventive component of edible cruciferous vegetables with in vivo efficacy against prostate cancer in experimental rodents. Cancer chemopreventive response to PEITC is characterized by its ability to inhibit multiple oncogenic signaling pathways, including nuclear factor-κB, Akt, and androgen receptor. The present study demonstrates, for the first time, that PEITC treatment activates Notch signaling in malignant as well as normal human prostate cells. 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, and increased transcriptional activity of Notch. In PC-3 and LNCaP cells, PEITC treatment caused induction of Notch ligands Jagged1 and Jagged2 (PC-3), overexpression of γ-secretase complex components Presenilin1 and Nicastrin (PC-3), nuclear enrichment of cleaved Notch2, and/or up-regulation of Notch1, Notch2, Jagged1, and/or Jagged2 mRNA. 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 knockdown of Notch2 protein as well as pharmacological inhibition of Notch1 activation. Nuclear expression of cleaved Notch2 protein was significantly higher in PC-3 xenografts from PEITC-treated mice and dorsolateral prostates from PEITC-fed TRAMP mice compared with 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 a Notch inhibitor.
Highlights
Practical and safe modalities for chemoprevention of prostate cancer are clinically attractive because of high mortality associated with this malignancy in American men [1]
The present study extends these observations [19,20,21,22] and examines the effect of Phenethyl isothiocyanate (PEITC) treatment on activation of Notch1 and Notch2, which belong to a family of transmembrane receptors implicated in prostate cancer development and metastasis [23], using cultured human prostate cancer cells (LNCaP, PC-3, LNCaP2C4-2, and DU145), a normal human prostate epithelial cell line (PrEC), PC-3 xenografts from control and PEITC-treated mice [13,16], and dorsolateral prostate from control and PEITCfed TRAMP mice [6]
In agreement with the results shown in cultured PC-3 cells (Fig. 3A) nuclear expression of cleaved Notch2 was significantly higher in PC-3 xenografts from PEITC-treated mice compared with control (Fig. 7A)
Summary
Practical and safe modalities for chemoprevention of prostate cancer are clinically attractive because of high mortality associated with this malignancy in American men [1]. 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 [3,4,5,6,7,8,9]. A population-based case-control study suggested an inverse association between intake of cruciferous vegetables and the risk of prostate cancer [4]. Growth of subcutaneous prostate cancer xenografts in athymic mice was significantly retarded by administration of PEITC or its N-acetylcysteine conjugate [10,11,12]. Oral PEITC administration augmented proapoptotic response to docetaxel in vivo in prostate cancer xenografts [13]
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