title: Allyl isothiocyanate arrests cancer cells in mitosis, and mitotic arrest in turn leads to apoptosis via Bcl-2 protein phosphorylation.
abstract: Allyl isothiocyanate (AITC) occurs in many commonly consumed cruciferous vegetables and exhibits significant anti-cancer activities. Available data suggest that it is particularly promising for bladder cancer prevention and/or treatment. Here, we show that AITC arrests human bladder cancer cells in mitosis and also induces apoptosis. Mitotic arrest by AITC was associated with increased ubiquitination and degradation of α- and β-tubulin. AITC directly binds to multiple cysteine residues of the tubulins. AITC induced mitochondrion-mediated apoptosis, as shown by cytochrome c release from mitochondria to cytoplasm, activation of caspase-9 and caspase-3, and formation of TUNEL-positive cells. Inhibition of caspase-9 blocked AITC-induced apoptosis. Moreover, we found that apoptosis induction by AITC depended entirely on mitotic arrest and was mediated via Bcl-2 phosphorylation at Ser-70. Pre-arresting cells in G(1) phase by hydroxyurea abrogated both AITC-induced mitotic arrest and Bcl-2 phosphorylation. Overexpression of a Bcl-2 mutant prevented AITC from inducing apoptosis. We further showed that AITC-induced Bcl-2 phosphorylation was caused by c-Jun N-terminal kinase (JNK), and AITC activates JNK. Taken together, this study has revealed a novel anticancer mechanism of a phytochemical that is commonly present in human diet.
authors.affiliation: Department of Cancer Prevention and Control, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Geng
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.forename: Kyoung-Soo
authors.initials: KS
authors.lastname: Choi
authors.forename: A Latif
authors.initials: AL
authors.lastname: Kazim
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c; D004789:Enzyme Activation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D017953:Isocyanates / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D000498:Allyl Compounds; D017953:Isocyanates; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin; C491149:allyl isocyanate; D045304:Cytochromes c; D048031:JNK Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D053453:Caspase 9