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.