Blockade of the RhoA-JNK-c-Jun-MMP2 Cascade by Atorvastatin Reduces Osteosarcoma Cell Invasion
Blockade of the RhoA-JNK-c-Jun-MMP2 Cascade by Atorvastatin Reduces Osteosarcoma Cell Invasion
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DOI：
10.1074/jbc.m801436200
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发表时间：
2008-11-07
影响因子：
4.8
通讯作者：
Marie, Pierre J.
中科院分区：
文献类型：
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作者：
Fromigue, Olivia;Hamidouche, Zahia;Marie, Pierre J.
骨肉瘤的特点是高恶性和转移潜力，这表明需要新的治疗策略来防止细胞转移。在这项研究中，我们表明，他汀类药物诱导的HMG-CoA还原酶抑制减少细胞迁移和侵袭的人类和小鼠骨肉瘤细胞，独立的基因型。他汀类药物诱导的细胞迁移和侵袭的减少是独立的诱导细胞凋亡和香叶基香叶基焦磷酸依赖。他汀类药物降低了侵袭细胞中基质金属蛋白酶（MMP）2、9和14以及TIMP 2的表达或活性。MMP 2和MMP 14的强制表达克服了他汀类药物对细胞侵袭的抑制作用，表明这些MMP在侵袭潜力中的作用。我们还研究了MMP 2活性降低和细胞侵袭的机制。抑制JNK而非ERK 1/2信号传导可降低MMP 2活性。JNK的药理学或组成性激活克服了他汀类药物诱导的MMP 2活性降低和细胞侵袭。他汀类药物降低JNK磷酸化和c-Jun核转位，表明HMG-CoA还原酶抑制作用靶向JNK-c-Jun信号通路。我们发现，甲羟戊酸或香叶基香叶基焦磷酸治疗阻止他汀类药物诱导的JNK磷酸化，MMP 2活性和细胞侵袭的减少。强制表达的组成型活性形式的RhoA增加JNK磷酸化，克服了阿托伐他汀对MMP 2活性和细胞侵袭的抑制作用。这些数据建立了RhoA、JNK、c-Jun和MMP 2活性之间的联系，MMP 2活性在功能上参与了他汀类药物减少骨肉瘤细胞侵袭。这表明了一种靶向RhoA-JNK-c-Jun信号传导以减少骨肉瘤细胞肿瘤发生的新策略。
Osteosarcoma is characterized by a high malignant and metastatic potential, which points to the need for new therapeutic strategies to prevent cell metastasis. In this study, we show that statin-induced HMG-CoA reductase inhibition reduces cell migration and invasion in human and murine osteosarcoma cells, independently of the genotype. The statin-induced reduction of cell migration and invasion was independent of induction of apoptosis and was geranylgeranylpyrophosphate-dependent. The statin reduced matrix metalloproteinase (MMP) 2, 9, and 14 and TIMP2 expression or activity in invading cells. Forced expression of MMP2 and MMP14 overcame the inhibitory effect of the statin on cell invasion, suggesting a role for these MMPs in invasive potential. We also investigated the mechanisms involved in the reduced MMP2 activity and cell invasion. Inhibition of JNK, but not ERK1/2 signaling, reduced MMP2 activity. Pharmacological or constitutive activation of JNK overcame the reduced MMP2 activity and cell invasion induced by the statin. The statin decreased JNK phosphorylation and c-Jun nuclear translocation, suggesting that HMG-CoA reductase inhibition targets the JNK-c-Jun signaling pathway. We showed that mevalonate or geranylgeranylpyrophosphate treatment prevented the statin-induced reduction in JNK phosphorylation, MMP2 activity, and cell invasion. Forced expression of a constitutively active form of RhoA increased JNK phosphorylation and overcame the inhibitory effect of atorvastatin on MMP2 activity and cell invasion. The data establish a link between RhoA, JNK, c-Jun, and MMP2 activity that is functionally involved in the reduction in osteosarcoma cell invasion by the statin. This suggests a novel strategy targeting RhoA-JNK-c-Jun signaling to reduce osteosarcoma cell tumorigenesis.