Phenylethyl isothiocyanate induces apoptotic signaling via suppressing phosphatase activity against c-Jun N-terminal kinase.
Dietary isothiocyanates induce apoptosis in various cancer cell lines through a c-Jun N-terminal kinase (JNK)-dependent mechanism. We found that phenylethyl isothiocyanate (PEITC) was capable of inducing JNK activation and apoptosis in prostate cancer cell lines with distinct p53 statuses. PEITC induced JNK-mediated apoptotic signaling via a different pathway than that used by DNA-damaging agents, because genotoxicresistant LNCaP prostate cancer cells were equally sensitive to PEITC as parental LNCaP cells. PEITC did not induce significant MKK4 or MKK7 activation and did not activate JNK directly, suggesting that JNK and JNK upstream kinases are not primary targets of PEITC. The JNK dephosphorylation and inactivation rates were decreased in cells exposed to PEITC. Expression levels of M3/6, a JNK-specific phosphatase, were down-regulated by PEITC via a proteasome-dependent mechanism. Taken together, our data suggest that PEITC activates JNK through suppression of JNK dephosphorylation and that PEITC may be an alternative therapeutic agent for cancers that are resistant to genotoxic agents. This study also reveals that JNK phosphatases are potential targets for the development of novel cancer therapeutic agents.
Chen
Yi-Rong
YR
Department of Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Han
Jin
J
Kori
Rajashree
R
Kong
A-N Tony
AN
Tan
Tse-Hua
TH
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011419:Propidium / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D017879:Isothiocyanates; D016159:Tumor Suppressor Protein p53; D011419:Propidium; C058305:phenethyl isothiocyanate; D000255:Adenosine Triphosphate; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases