Dietary isothiocyanate mediated apoptosis of human cancer cells is associated with Bcl-xL phosphorylation.
Benzylisothiocyanate (BITC), a major phase II enzyme inducer in the organic solvent of papaya fruit, has been shown to induce apoptosis specifically in cancer cells. The exposure of pancreatic, prostate as well as leukemic cells to this dietary isothiocyanate resulted in significant extent of apoptosis as evident from PARP cleavage, chromatin condensation or profound attenuation of procaspase-3 level. We also investigated whether BITC induces apoptosis by converging two major pathways: the death receptor mediated extrinsic and the mitochondrial intrinsic pathway. The exogenous expression of dominant-negative caspase-8 or dominant-negative caspase-9 can attenuate BITC-mediated cell death of prostate cancer cells. In parallel with this observation, BITC can activate both procaspase-8 and -9 in pancreatic and prostate cancer cells. Furthermore, flow cytometry analysis demonstrated the enrichment of sub-G0-G1 phase population with G2-M arrest in BITC challenged pancreatic cancer cells. In order to comprehend the molecular mechanism underlying the relationship between BITC-mediated cell cycle arrest and apoptosis we report here for the first time that the anti-apoptotic protein Bcl-xL was phosphorylated by BITC treatment. Subsequent investigation using Jun kinase inhibitor exhibits the involvement of Jun kinase in BITC triggered Bcl-xL phosphorylation and apoptosis.
Basu
Aruna
A
Center for Biomedical Sciences, Department of Pharmacology, Case Comprehensive Cancer Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH, USA.
Haldar
Subrata
S
D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005638:Fruit; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D008954:Models, Biological; D009369:Neoplasms / Q000178:diet therapy* / Q000188:drug therapy / Q000473:pathology*; D010766:Phosphorylation; D051020:bcl-X Protein / Q000378:metabolism*
D004791:Enzyme Inhibitors; D017879:Isothiocyanates; D051020:bcl-X Protein; C031403:benzyl isothiocyanate; D053181:Caspase 8; D053453:Caspase 9