15-Lipoxygenase-1/15-hydroxyeicosatetraenoic acid promotes hepatocellular cancer cells growth through protein kinase B and heat shock protein 90 complex activation

Hepatocellular carcinoma is a typical hypervascular tumor resulted from excessive growth of tumor cells. Previous studies have demonstrated that the lipoxygenase is considered as a potential therapeutic target and have important influence on human cancers. However, whether the 15-lipoxygenase-1 (15-LO-1)/15-hydroxyeicosatetraenoic acid (15-HETE) pathway participates in the development and progression of hepatocellular carcinoma has not been reported until now. To test the hypothesis that the 15-LO-1/15-HETE signaling regulates hepatocellular carcinoma cells growth and metastasis via the phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt)/heat shock protein 90 pathway, we performed these studies. Our results showed that hepatocellular carcinoma cell lines (HepG2 and SMMC7721) apoptosis and growth arrest occurred following blockade of the 15-LO pathway with a 15-LO-1 inhibitor or siRNA, and all the effects were reversed by exogenous 15-HETE. Meanwhile, 15-HETE strengthened the expression of phosphor-Akt and heat shock protein 90, and inhibited apoptosis induced by serum deprivation via promoting the interaction of Ala with heat shock protein 90. In addition, the invasion and migration of HepG2 enhanced by 15-HETE were both attenuated by the inhibitor of Akt or heat shock protein 90. These results indicate that the 15-LO-1/15-HETE pathway prevents hepatocellular carcinoma cells from apoptosis and promotes hepatocellular carcinoma progression via a specific intracellular signaling pathway centered by the interaction of Ala with heat shock protein 90, and suggest a new therapeutic target for hepatocellular carcinoma. (C) 2013 Elsevier Ltd. All rights reserved.

肝细胞癌是一种由肿瘤细胞过度生长导致的典型富血管肿瘤。先前的研究表明，脂氧合酶被视为一个潜在的治疗靶点，并且对人类癌症具有重要影响。然而，直到现在，15 - 脂氧合酶 - 1（15 - LO - 1）/15 - 羟基二十碳四烯酸（15 - HETE）通路是否参与肝细胞癌的发生和发展尚未见报道。为了验证15 - LO - 1/15 - HETE信号通过磷脂酰肌醇 - 3激酶（PI3K）/蛋白激酶B（Akt）/热休克蛋白90通路调节肝细胞癌细胞生长和转移这一假说，我们进行了这些研究。我们的结果显示，用15 - LO - 1抑制剂或小干扰RNA阻断15 - LO通路后，肝细胞癌细胞系（HepG2和SMMC7721）出现凋亡和生长停滞，并且所有这些效应都可被外源性15 - HETE逆转。同时，15 - HETE增强了磷酸化Akt和热休克蛋白90的表达，并通过促进Ala与热休克蛋白90的相互作用抑制血清剥夺诱导的凋亡。此外，15 - HETE增强的HepG2的侵袭和迁移都可被Akt或热休克蛋白90的抑制剂减弱。这些结果表明，15 - LO - 1/15 - HETE通路通过以Ala与热休克蛋白90相互作用为核心的特定细胞内信号通路阻止肝细胞癌细胞凋亡并促进肝细胞癌进展，并为肝细胞癌提出了一个新的治疗靶点。（C）2013爱思唯尔有限公司。保留所有权利。