P38 MAPK activation selectively induces cell death in K-ras-mutated human colon cancer cells through regulation of vitamin D receptor
P38 MAPK activation selectively induces cell death in K-ras-mutated human colon cancer cells through regulation of vitamin D receptor
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DOI：
10.1074/jbc.m313964200
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发表时间：
2004-05-21
影响因子：
4.8
通讯作者：
Chen, G
中科院分区：
文献类型：
--
作者：
Qi, XM;Tang, J;Chen, G
ras是人类癌症中最具特征的癌基因，然而没有选择性靶向该癌基因的有效治疗剂。我们先前的工作证明了p38途径在实验NIH 3 T3细胞中Ras增殖信号传导中的抑制活性（Chen，G.，Hitomi，M.，汉，J.，和Stacey，D. W.（2000）J.Biol.Chem.275，38973-38980）。在这里，我们探讨了p38激酶激活在人结肠癌细胞与内源性K-ras激活和不激活的治疗潜力。通过腺病毒介导的组成型活性p38激活剂MKK 6的基因递送和亚砷酸盐的p38激活选择性地诱导K-ras激活的人结肠癌HCT 116细胞的细胞死亡，但不诱导K-ras破坏的HCT 116衍生的亚系的细胞死亡。MKK 6的细胞死亡诱导作用不是因为其选择性激活K-ras激活细胞中的p38激酶或其下游转录因子底物ATF-2或c-Jun。相反，K-ras激活细胞的细胞死亡与AP-1依赖性机制引起的维生素D受体（VDR）下调有关。在K-ras激活的细胞中强制VDR表达抑制p38激活诱导的细胞死亡，并且在K-ras破坏的细胞中抑制内源性VDR蛋白表达增加亚砷酸盐诱导的毒性。对另外两种具有和不具有K-ras突变的人结肠癌细胞系的分析也显示了MKK 6的K-ras和VDR依赖性毒性。因此，p38通路激活通过涉及VDR活性抑制的机制选择性地诱导K-ras突变的人结肠癌细胞中的细胞死亡。
ras is the most characterized oncogene in human cancer, and yet there are no effective therapeutics to selectively target this oncogene. Our previous work demonstrated the inhibitory activity of the p38 pathway in Ras proliferative signaling in experimental NIH 3T3 cells (Chen, G., Hitomi, M., Han, J., and Stacey, D. W. (2000) J. Biol. Chem. 275, 38973-38980). Here we explore the therapeutic potential of p38 kinase activation in human colon cancer cells with and without endogenous K-ras activation. p38 activation by both adenovirus-mediated gene delivery of constitutively active p38 activator MKK6 and by arsenite selectively induces cell death in K-ras-activated human colon cancer HCT116 cells but not in the K-ras-disrupted HCT116-derived sublines. The cell death-inducing effect of MKK6 is not because of its selective activation of p38 kinase or its downstream transcription factor substrates, ATF-2 or c-Jun, in K-ras-activated cells. Rather, cell death in K-ras-activated cells is linked to the down-regulation of vitamin D receptor (VDR) by an AP-1-dependent mechanism. Forced VDR expression in K-ras-activated cells inhibits p38 activation-induced cell death, and inhibition of endogenous VDR protein expression in K-ras-disrupted cells increased the arsenite-induced toxicity. Analysis of an additional two human colon cancer cell lines with and without K-ras mutation also showed a K-ras- and VDR-dependent toxicity of MKK6. Hence, p38 pathway activation selectively induces cell death in K-ras- mutated human colon cancer cells by mechanisms involving the suppression of VDR activity.