Xiao Dong, Singh Shivendra V
Department of Pharmacology and the University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Cancer Res. 2002 Jul 1;62(13):3615-9.
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.
先前的研究表明，苯乙基异硫氰酸酯（PEITC）诱导细胞凋亡需要p53，PEITC是一种极具前景的癌症化学预防剂。在此，我们报告在PC-3人前列腺癌细胞系中，PEITC诱导的细胞凋亡不需要p53，且PEITC诱导的细胞凋亡是由细胞外信号调节激酶（ERK1/2）介导的。将PC-3细胞暴露于诱导凋亡浓度的PEITC（10微摩尔）导致ERK1/2迅速且持续激活，早在PEITC处理后1小时就很明显，并在实验期间（PEITC暴露后24小时）持续存在。PEITC介导的ERK1/2激活与其底物Elk-1在Ser383处的磷酸化增加有关。在有丝分裂原激活蛋白/ERK激酶1（ERK1/2上游的一种激酶）抑制剂PD98059存在的情况下，PEITC诱导的ERK1/2激活以及细胞凋亡被消除。将PC-3细胞暴露于10微摩尔PEITC还导致p38蛋白激酶的时间依赖性激活，这与激活转录因子2在Thr71处的磷酸化增加有关。尽管在其特异性抑制剂SB202190存在的情况下，PEITC诱导的p38蛋白激酶激活被废除，但抑制p38蛋白激酶激活并不能阻止PEITC诱导的细胞凋亡。与先前在其他细胞系统中的报道相反，在PC-3人前列腺癌细胞系中，PEITC处理并未激活c-Jun氨基末端激酶。总之，本研究结果表明p53对于PEITC诱导的细胞凋亡并非必不可少，且在PC-3人前列腺癌细胞系中，PEITC诱导的细胞凋亡是由ERK介导的。因此，推测PEITC可能对具有正常p53以及突变p53的肿瘤均有效似乎是合理的。
