Anti-proliferative and proapoptotic effects of benzyl isothiocyanate on human pancreatic cancer cells is linked to death receptor activation and RasGAP/Rac1 down-modulation.
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 up-regulation 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.
Basu
Aruna
A
MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109, USA. abasu@metrohealth.org
Haldar
Subrata
S
D000230:Adenocarcinoma / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D017879:Isothiocyanates; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; D020703:ras GTPase-Activating Proteins; C031403:benzyl isothiocyanate; D020830:rac1 GTP-Binding Protein