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: Feng Geng, Li Tang, Yun Li, Lu Yang, Kyoung-Soo Choi, A Latif Kazim, Yuesheng Zhang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 37 Pg. 32259-67 (Sep 16 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21778226 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Allyl Compounds
• Isocyanates
• Proto-Oncogene Proteins c-bcl-2
• Tubulin
• allyl isocyanate
• Cytochromes c
• JNK Mitogen-Activated Protein Kinases
• CASP3 protein, human
• Caspase 3
• Caspase 9

Topics

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