Selective inhibition of cancer cell invasion by a geranylgeranyltransferase-I inhibitor
Selective inhibition of cancer cell invasion by a geranylgeranyltransferase-I inhibitor
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DOI：
10.1023/a:1025898316728
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发表时间：
2003-01-01
影响因子：
4
通讯作者：
Inoue, M
中科院分区：
文献类型：
--
作者：
Kusama, T;Mukai, M;Inoue, M
一些小的gtpase参与了癌细胞的增殖、迁移和侵袭。它们需要被戊烯化才能发挥完整的生物学功能。我们最近报道了3-羟基-3-甲基戊二酰辅酶A （HMG-CoA）还原酶抑制剂，阻断法尼基焦磷酸和香叶基焦磷酸的生物合成，抑制人胰腺癌细胞的体外侵袭。在本研究中，我们通过改进的Boyden室实验检测了两种选择性戊烯酰化抑制剂，一种法尼基转移酶抑制剂（FTI-277）和一种香叶基转移酶I型抑制剂（GGTI-298）对癌细胞体外侵袭的影响。HMG-CoA还原酶抑制剂洛伐他汀和GGTI-298对COLO 320DM人结肠癌细胞的侵袭有较强的抑制作用，而FTI-277对COLO 320DM人结肠癌细胞的侵袭作用较弱。GGTI-298对肿瘤细胞的作用显著导致RhoA在膜部分减少，在胞质部分积聚，而对Ras易位几乎没有影响。FTI-277明显抑制Ras的膜定位，但其对癌细胞侵袭的抑制作用仅发生在影响RhoA膜定位的剂量下。FTI-277和GGTI-298降低COLO 320DM细胞的生长潜能，但GGTI-298对侵袭的抑制作用具有选择性，与细胞形态和RhoA定位的改变有关。这些结果表明，香叶基香叶基转移酶I对RhoA的香叶基化作用对癌细胞的侵袭至关重要，抑制香叶基转移酶I的活性将为治疗对香叶基转移酶抑制剂有抗性的癌细胞的侵袭和转移提供一种新的途径。
A number of small GTPases are involved in cancer cell proliferation, migration and invasion. They need to be prenylated for full biological functions. We have recently reported that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, which block the biosynthesis of farnesylpyrophosphate and geranylgeranylpyrophosphate, inhibit in vitro invasion of human pancreatic cancer cells. In the present study, we examined the effects of two selective inhibitors of prenylation, a farnesyltransferase inhibitor (FTI-277) and a geranylgeranyltransferase type I inhibitor (GGTI-298), on in vitro invasion of cancer cells in a modified Boyden chamber assay. The invasion of COLO 320DM human colon cancer cells was inhibited potently by HMG-CoA reductase inhibitor lovastatin and GGTI-298 but weakly by FTI-277. The treatment of cancer cells with GGTI-298 markedly caused RhoA to decrease in the membrane fraction and accumulate in the cytosolic fraction, whereas it had almost no effect on the translocation of Ras. FTI-277 markedly inhibited membrane localization of Ras, but its inhibitory effect on cancer cell invasion occurred only at doses that affected membrane localization of RhoA. FTI-277 and GGTI-298 decreased the growth potential of COLO 320DM cells, but the inhibitory effect of GGTI-298 was rather selective toward invasion in association with changes in cell morphology and RhoA localization. These results suggest that geranylgeranylation of RhoA by geranylgeranyltransferase type I is critical for cancer cell invasion, and inhibition of geranylgeranyltransferase type I activity should offer a novel approach to the treatment of invasion and metastasis of cancer cells resistant to farnesyltransferase inhibitors.