Kusama T, Mukai M, Iwasaki T, Tatsuta M, Matsumoto Y, Akedo H, Nakamura H
Department of Tumor Biochemistry, Gastrointestinal Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan.
Cancer Res. 2001 Jun 15;61(12):4885-91.
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors prevent the conversion of HMG-CoA to mevalonate and thereby inhibit the synthesis of other products derived from this metabolite. This includes a number of small prenylated GTPases involved in cell growth, motility, and invasion. We studied the effect of HMG-CoA reductase inhibitors (fluvastatin and lovastatin) on in vitro invasion of human pancreatic cancer PANC-1 cells. Epidermal growth factor (EGF) induced a dose-dependent increase of PANC-1 cell invasion in a modified Boyden chamber assay. Stimulation of cancer cells with EGF induced translocation of RhoA from the cytosol to the membrane fraction and actin stress fiber assembly. Furthermore, Clostridium botulinum C3 transferase, a specific inhibitor of Rho, inhibited the ability of EGF to promote invasion, indicating that EGF-induced cancer cell invasion is regulated by Rho signaling. Treatment of PANC-1 cells with fluvastatin markedly attenuated EGF-induced translocation of RhoA from the cytosol to the membrane fraction and actin stress fiber assembly, whereas it did not inhibit the tyrosine phosphorylation of EGF receptor and c-erbB-2. The induction of cancer cell invasion by EGF was inhibited by the addition of fluvastatin or lovastatin in a dose-dependent manner. The effects of fluvastatin or lovastatin on cell morphology and invasion were reversed by the addition of all-trans-geranylgeraniol but not by the addition of all-trans-farnesol. These results suggest that HMG-CoA reductase inhibitors affect RhoA activation by preventing geranylgeranylation, which results in inhibition of EGF-induced invasiveness of human pancreatic cancer cells.
3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂可阻止HMG-CoA转化为甲羟戊酸，从而抑制源自该代谢产物的其他产物的合成。这包括一些参与细胞生长、运动和侵袭的小的异戊二烯化GTP酶。我们研究了HMG-CoA还原酶抑制剂（氟伐他汀和洛伐他汀）对人胰腺癌细胞PANC-1体外侵袭的影响。在改良的Boyden小室试验中，表皮生长因子（EGF）诱导PANC-1细胞侵袭呈剂量依赖性增加。用EGF刺激癌细胞可诱导RhoA从胞质溶胶转位至膜部分并形成肌动蛋白应力纤维。此外，肉毒杆菌C3转移酶（一种Rho的特异性抑制剂）可抑制EGF促进侵袭的能力，表明EGF诱导的癌细胞侵袭受Rho信号调控。用氟伐他汀处理PANC-1细胞可显著减弱EGF诱导的RhoA从胞质溶胶转位至膜部分以及肌动蛋白应力纤维的形成，而它并不抑制EGF受体和c-erbB-2的酪氨酸磷酸化。添加氟伐他汀或洛伐他汀可剂量依赖性地抑制EGF诱导的癌细胞侵袭。添加全反式香叶基香叶醇可逆转氟伐他汀或洛伐他汀对细胞形态和侵袭的影响，而添加全反式法尼醇则不能。这些结果表明，HMG-CoA还原酶抑制剂通过阻止香叶基香叶基化来影响RhoA激活，从而导致抑制EGF诱导的人胰腺癌细胞侵袭性。
