3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis
3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis
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DOI：
10.1053/gast.2002.31093
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发表时间：
2002-02-01
期刊：
影响因子：
29.4
通讯作者：
Nakamura, H
中科院分区：
文献类型：
--
作者：
Kusama, T;Mukai, M;Nakamura, H
背景和目标：3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的抑制阻断了甲羟戊酸代谢途径，这是许多小的鸟苷三磷酸酶的异戊二烯化所必需的。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体外侵袭和体内实验性肝转移的影响。方法：采用改良的Boyden小室法检测细胞侵袭能力。通过免疫印迹评估RhoA的易位。通过脾内接种ASPC-1人胰腺癌细胞诱导裸鼠实验性肝转移。结果氟伐他汀和洛伐他汀对表皮生长因子（EGF）诱导的癌细胞体外侵袭具有抑制作用，且对Rho的特异性抑制剂C3转移酶敏感。ASPC-1细胞与氟伐他汀治疗显着衰减EGF诱导的RhoA从胞质到膜组分的易位，并引起细胞变圆。氟伐他汀的作用可被全反式香叶基香叶醇逆转。在推荐用于治疗人类高胆固醇血症的剂量下，给予裸鼠氟伐他汀可减少肝脏中转移性肿瘤的形成和已建立的肝转移瘤的生长。结论：HMG-CoA还原酶抑制剂是一种具有潜在临床应用价值的抗肿瘤转移药物。
Background & Aims: Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase blocks the mevalonate metabolic pathway, which is necessary for the isoprenylation of a number of small guanosine triphosphatases. We examined the effects of HMG-CoA reductase inhibitors, fluvastatin and lovastatin, on human pancreatic cancer cell invasion in vitro and experimental liver metastasis in vivo. Methods: Cell invasion was studied in a modified Boyden chamber assay. The translocation of RhoA was assessed by immunoblotting. Experimental liver metastases were Induced in nude mice by intrasplenic inoculation of ASPC-1 human pancreatic cancer cells. Results. Fluvastatin and lovastatin inhibited the in vitro cancer cell invasion induced by epidermal growth factor (EGF) in a manner sensitive to C3 transferase, a specific inhibitor of Rho. Treatment of ASPC-1 cells with fluvastatin markedly attenuated the EGF-induced translocation of RhoA from the cytosol to the membrane fraction and caused cell rounding. The effects of fluvastatin could be reversed by the addition of all-trans-geranylgeraniol. Administration of fluvastatin to nude mice reduced both metastatic tumor formation in the liver and the growth of established liver metastases at doses recommended for the treatment of hypercholesterolemia in humans. Conclusions: HMG-CoA reductase inhibitors can be antimetastatic agents with the potential for useful clinical applications.