Anti-proliferative and proapoptotic effects of benzyl isothiocyanate on human pancreatic cancer cells is linked to death receptor activation and RasGAP/Rac1 down-modulation

Abstract

Abstract. Benzyl isothiocyanate can exert anti-tumor effect by arrest of cell cycle progression and induction of apoptosis in human pancreatic cancer cells. Among them, the dissection of the molecular mechanism of induction of apoptosis is important because the knowledge may be exploited for both cancer prevention and treatment. Our studies reported here indicate that BITC-mediated apoptosis involves the disappearance of intact 21-kDa Bid protein, cytochrome c release and predominant procaspase-3 cleavage. Using adenocarcinoma and metastatic pancreatic cancer cells, we investigated whether this dietary isothiocyanate induces apoptosis by converging two major pathways: the death receptor-mediated extrinsic and the mitochondrial intrinsic pathway. Indeed, cell surface receptor analysis by flow cytometry demonstrates the upregulation of DR4, a member of death receptor family in BITC exposed pancreatic cancer cells. Since BITC is able to trigger death receptor signaling, we were interested in examining the effects of BITC and death receptor ligand TRAIL together on pancreatic cancer cell death. Interestingly, BITC augments TRAIL-induced apoptosis in both metastatic and adenocarcinoma cells. Moreover, we report for the first time that the sensitivity of metastatic pancreatic cancer cells to this isothiocyanate might be due to down-modulation of the proangiogenic molecule small GTPase Rac1 and caspase-3 substrate RasGAP, a regulator of Rho GTPase family.

MicroRNA-375 and MicroRNA-221: Potential Noncoding RNAs Associated with Antiproliferative Activity of Benzyl Isothiocyanate in Pancreatic Cancer

“…Previous reports reveal that the chemopreventive agent BITC has the potency to inhibit the growth of pancreatic cancer cells by exerting antiproliferative effects in vitro. 17,18,27 However, these effects can be mediated by the crossover of multiple signaling pathways. BITC might behave as an agent that is capable of intervening simultaneously at several targets in the carcinogenic process.…”

MicroRNA-mediated regulation of pancreatic cancer cell proliferation

“…The medium was changed every 4 days. The cells were then fixed with 4% buffered formalin (Electron Microscopy Sciences, Hatfield, PA, USA) and stained with 0.1% crystal violet for visualization and photography (19,20). (Fig.…”

“…1B). The clonogenic cell survival assay (19,20) was employed to determine the long-term survival ability of BxPC-3 cells following transfection with miR-16 and its inhibitor oligos. Notably, the overexpression of miR-16 significantly decreased the clonogenic cell survival of pancreatic tumor cells when compared to the mimic negative control (Fig.…”

TRAIL Mediated Signaling in Pancreatic Cancer

“…Gimatecan, a potent lipophilic camptothecin has earlier been tested for efficacy in combination with CpGoligodeoxynucleotides in pancreatic cancer xenograft (Petrangolini et al, 2008 DOI:http://dx.doi.org/10.7314/APJCP.2014.15.15.5977 TRAIL Mediated Signaling in Pancreatic Cancer via inhibition of Rac1 in pancreatic ductal carcinoma cells CFPAC-1 (Basu and Haldar, 2009 (Haag et al, 2011). Triptolide, a diterpene triepoxide improved TRAIL mediated apoptosis in pancreatic cancer cells via upregulation of DR5 and downregulation of c-FLIP .…”