Abstract
Benzyl isothiocyanate (BITC) in cruciferous plants, which are part of the human diet, has been shown to induce apoptosis in various types of cancer. In this study, we show that BITC effectively suppresses the growth of cultured human prostate cancer cells (CRW-22Rv1 and PC3) by causing mitochondrial membrane potential loss, caspase 3/7 activation and DNA fragmentation. Furthermore, BITC induces ROS generation in these cells. The induction of apoptosis by BITC was significantly attenuated in the presence of N-acetylcysteine (NAC) and catalase (CAT), well-studied ROS scavengers. The induction of autophagy in BITC-treated cells were also diminished by the application of NAC or CAT. In addition, BITC-induced apoptosis and autophagy were both enhanced by the pretreatment of catalase inhibitor, 3-Amino-1,2,4-triazole (3-AT). Pretreatment with specific inhibitors of autophagy (3-methyladenine or bafilomycin A1) or apoptosis (Z-VAD-FMK) reduced BITC-induced autophagy and apoptosis, respectively, but did not abolish BITC-induced ROS generation. In conclusion, the present study provides evidences that BITC caused prostate cancer cell death was dependent on the ROS status, and clarified the mechanism underlying BITC-induced cell death, which involves the induction of ROS production, autophagy and apoptosis, and the relationship between these three important processes.
Highlights
Epidemiologic studies continue to support that dietary intake of cruciferous vegetables may reduce the risk of various types of malignancies including prostate cancer [1, 2]
We revealed that Benzyl isothiocyanate (BITC) effectively reduces the viability of prostate cancer cells, similar to other cellular systems [26, 38,39,40,41], via the www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget induction of apoptosis, which is involved in the disruption of the membrane potential (MMP), the activation of caspase 3/7 and an increase in DNA fragmentation (Figure 1)
We report that BITC induces ROS generation in both hormone-sensitive (Rv1) and hormone-refractory (PC3) human prostate cancer cells (Figure 2)
Summary
Epidemiologic studies continue to support that dietary intake of cruciferous vegetables may reduce the risk of various types of malignancies including prostate cancer [1, 2]. Research over the past decade has shown that the molecular mechanism by which apoptosis is induced by BITC is complex and utilizes a wide range of signaling pathways that induce alterations including the expression of anti-apoptotic Bcl-2 family proteins, the activation of mitogen-activated protein kinases, the suppression of oncogenic signaling and the activation of caspases, the common link in apoptosis induction by BITC and other ITCs is the production of reactive oxygen species (ROS) [5]. It is interesting that BITC, phenethyl ITC (PEITC) and sulforaphane (SFN) induce apoptosis in cancer cells but not in normal epithelial cells [8, 16, 17]. PEITC has been shown to differentially alter the expression of oxidative stress- and antioxidant defense-related genes in a prostate cancer cell line (PC3) and in a normal prostate epithelial cell line (PrEC) [18]; the mechanism underlying the differential sensitivity of cancer and normal cell types to apoptosis induced by ITCs remains unclear
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