Chang M Y, Jan M S, Won S J, Liu H S
Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China.
Biochem Biophys Res Commun. 1998 Jul 9;248(1):62-8. doi: 10.1006/bbrc.1998.8911.
This study demonstrates that Ha-rasVal12 oncogene overexpression sensitizes NIH/3T3 fibroblasts to lovastatin (LOV) cytotoxicity. This sensitization is through apoptosis, which was characterized by increasing CPP32 (caspase-3) activity and DNA fragmentation. Bcl-2 overexpression increased the resistance of the Ha-ras transformants to LOV and rescued the cells from apoptosis, further confirming that the LOV-sensitive cells died of apoptosis. Further analysis showed that Ha-ras activity inversely correlated with WAF1 activity. LOV treatment suppressed Ha-ras activity but induced WAF1 activity and disrupted the cell population in G0/G1 and S phases. The Ha-ras transformants expressing either dominant negative RasAsn17 or Raf-1CB4 showed reverted susceptibility to LOV. These data confirm the involvement of Ras and demonstrate that Raf-1 signalling is required for LOV-induced cell death. Taken together, the possible action of LOV-induced apoptosis is through suppressing Ha-ras activity and increasing WAF1 activity, which alters cell cycle progression and finally activates suppressed apoptotic pathway in a Fas/Fas-L- and p53-independent fashion.
本研究表明，Ha-rasVal12癌基因的过表达使NIH/3T3成纤维细胞对洛伐他汀（LOV）的细胞毒性敏感。这种敏感性是通过凋亡实现的，其特征是CPP32（半胱天冬酶-3）活性增加和DNA片段化。Bcl-2的过表达增加了Ha-ras转化细胞对LOV的抗性，并使细胞免于凋亡，进一步证实了对LOV敏感的细胞死于凋亡。进一步分析表明，Ha-ras活性与WAF1活性呈负相关。LOV处理抑制Ha-ras活性，但诱导WAF1活性，并扰乱G0/G1期和S期的细胞群体。表达显性负性RasAsn17或Raf-1CB4的Ha-ras转化细胞对LOV的敏感性恢复。这些数据证实了Ras的参与，并表明Raf-1信号传导是LOV诱导细胞死亡所必需的。综上所述，LOV诱导凋亡的可能作用是通过抑制Ha-ras活性和增加WAF1活性，从而改变细胞周期进程，并最终以不依赖Fas/Fas-L和p53的方式激活受抑制的凋亡途径。
