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Allyl isothiocyanate arrests cancer cells in mitosis, and mitotic arrest in turn leads to apoptosis via Bcl-2 protein phosphorylation.

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.

Pubmed ID: 21778226

Authors

  • Geng F
  • Tang L
  • Li Y
  • Yang L
  • Choi KS
  • Kazim AL
  • Zhang Y

Journal

The Journal of biological chemistry

Publication Data

September 16, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: R01CA124627

Mesh Terms

  • Allyl Compounds
  • Apoptosis
  • Caspase 3
  • Caspase 9
  • Cell Line, Tumor
  • Cytochromes c
  • Enzyme Activation
  • G1 Phase
  • Humans
  • Isocyanates
  • JNK Mitogen-Activated Protein Kinases
  • Mitochondria
  • Mitosis
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcl-2
  • Tubulin
  • Ubiquitination
  • Urinary Bladder Neoplasms