REVERSAL OF RAS-INDUCED INHIBITION OF GAP-JUNCTIONAL INTERCELLULAR COMMUNICATION, TRANSFORMATION, AND TUMORIGENESIS BY LOVASTATIN
REVERSAL OF RAS-INDUCED INHIBITION OF GAP-JUNCTIONAL INTERCELLULAR COMMUNICATION, TRANSFORMATION, AND TUMORIGENESIS BY LOVASTATIN
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DOI：
10.1002/mc.2940070109
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发表时间：
1993-01-01
影响因子：
4.6
通讯作者：
KLAUNIG, JE
中科院分区：
文献类型：
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作者：
RUCH, RJ;MADHUKAR, BV;KLAUNIG, JE
ras癌蛋白p21的质膜结合和转化活性依赖于翻译后法尼基化。法尼基合成和p21 ras法尼基化被羟甲基戊二酰辅酶A还原酶抑制剂如洛伐他汀抑制。在这项研究中，我们研究了洛伐他汀是否可以逆转转化表型的v-Ha-ras转化的大鼠肝上皮细胞系（WB-ras细胞），如果变化与间隙连接细胞间通讯（GJIC）的增强。WB-ras细胞在软琼脂中生长，GJIC减少，并且具有高度致瘤性。用洛伐他汀（0.1-0.5 μ M）体外处理48小时后，这些细胞中p21 ras的膜结合受到抑制。同时，细胞显示出更正常的形态，在软琼脂中生长减少，GJIC增强。与甲羟戊酸共同治疗可预防这些变化。其他癌基因（SRC、neu和raf/myc）转化的大鼠肝上皮细胞的形态学和GJIC不受洛伐他汀的影响。通过门静脉注射WB-ras细胞在雄性大鼠中诱导肝内WB-ras肿瘤。这些肿瘤的大小和DNA标记指数下降约75%的洛伐他汀（5毫克/公斤口服2周，每天两次）。这些结果表明，洛伐他汀逆转WB-ras细胞的转化表型通过抑制p21 ras质膜结合。此外，伴随着增强的GJIC在lovastatin处理的细胞表明减少GJIC的转化表型的表达中的作用。
The plasma-membrane association and transforming activity of the ras oncoprotein p21 are dependent upon posttranslational farnesylation. Farnesyl synthesis and p21 ras farnesylation are inhibited by hydroxymethylglutaryl-CoA reductase inhibitors such as lovastatin. In this study, we examined whether lovastatin could reverse the transformed phenotype of a v-Ha-ras-transformed rat liver epithelial cell line (WB-ras cells) and if changes were associated with the enhancement of gap-junctional intercellular communication (GJIC). WB-ras cells grow in soft agar, have reduced GJIC, and are highly tumorigenic. Membrane association of p21 ras in these cells was inhibited after in vitro treatment with lovastatin (0.1-0.5 muM) for 48 h. Concomitantly, the cells displayed a more normal morphology, decreased growth in soft agar, and enhanced GJIC. These changes were prevented by cotreatment with mevalonic acid. The morphology and GJIC of rat liver epithelial cells transformed with other oncogenes (src, neu, and raf/myc) were not affected by lovastatin. Intrahepatic WB-ras tumors were induced in male rats by intraportal-vein injection of WB-ras cells. The size and DNA labeling index of these tumors were decreased approximately 75% by administration of lovastatin (5 mg/kg orally twice daily for 2 wk). These results suggest that lovastatin reversed the transformed phenotype of WB-ras cells by inhibiting p21 ras plasma membrane association. Furthermore, the concomitant enhancement of GJIC in lovastatin-treated cells suggests a role for reduced GJIC in the expression of the transformed phenotype.