Phenethyl isothiocyanate-induced apoptosis in p53-deficient PC-3 human prostate cancer cell line is mediated by extracellular signal-regulated kinases.

Abstract

Previous studies have suggested that p53 is required for apoptosis induction by phenethyl isothiocyanate (PEITC), which is a highly promising cancer chemopreventive agent. Here, we report that p53 is not required for PEITC-induced apoptosis in the PC-3 human prostate cancer cell line and that the PEITC-induced apoptosis is mediated by extracellular signal-regulated kinases (ERK1/2). Exposure of PC-3 cells to an apoptosis-inducing concentration of PEITC (10 microM) resulted in a rapid and sustained activation of ERK1/2 that was evident as early as 1 h after PEITC treatment and persisted for the duration of the experiment (24-h after PEITC exposure). The PEITC-mediated activation of ERK1/2 was associated with an increase in phosphorylation of its substrate Elk-1 at Ser383. The PEITC-induced activation of ERK1/2 as well as apoptosis was abolished in the presence of mitogen-activated protein/ERK kinase 1 (a kinase upstream of ERK1/2) inhibitor PD98059. Exposure of PC-3 cells to 10 microM PEITC also resulted in a time-dependent activation of p38 protein kinase that was associated with increased phosphorylation of activating transcription factor 2 at Thr71. Even though the PEITC-induced activation of p38 protein kinase was abrogated in the presence of its specific inhibitor SB202190, inhibition of p38 protein kinase activation did not prevent PEITC-induced apoptosis. In contrast to previous reports in other cellular systems, c-Jun NH(2)-terminal kinases were not activated by PEITC treatment in PC-3 human prostate carcinoma cell line. In conclusion, the results of the present study indicate that p53 is not essential for PEITC-induced apoptosis and that the PEITC-induced apoptosis in PC-3 human prostate carcinoma cell line is mediated by ERKs. Thus, it seems reasonable to postulate that PEITC may be effective against tumors with normal as well as mutant p53.

• Authors: Dong Xiao, Shivendra V Singh
• Journal: Cancer research (Cancer Res) Vol. 62 Issue 13 Pg. 3615-9 (Jul 01 2002) ISSN: 0008-5472 [Print] United States
• PMID: 12097262 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anticarcinogenic Agents
• Isothiocyanates
• Tumor Suppressor Protein p53
• phenethyl isothiocyanate
• Protein Serine-Threonine Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 1
• MAP2K1 protein, human
• Mitogen-Activated Protein Kinase Kinases

Topics

• Anticarcinogenic Agents (pharmacology)
• Apoptosis (drug effects, physiology)
• Enzyme Activation
• Humans
• Isothiocyanates (pharmacology)
• MAP Kinase Kinase 1
• Male
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Phosphorylation
• Prostatic Neoplasms (drug therapy, enzymology, pathology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (deficiency)
• p38 Mitogen-Activated Protein Kinases