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

• Published in: The international journal of biochemistry & cell biology Vol. 45; no. 6; pp. 1031 - 1041
• Main Authors: Ma, Jun, Zhang, Lei, Zhang, Jianguo, Liu, Mengmeng, Wei, Liuping, Shen, Tingting, Ma, Cui, Wang, Yanyan, Chen, Yingli, Zhu, Daling
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.06.2013
• Subjects: 15-Hydroxyeicosatetraenoic acid; 15-Lipoxygenase-1; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Arachidonate 15-Lipoxygenase - genetics; Arachidonate 15-Lipoxygenase - metabolism; blood serum; Cancer; cell growth; Cell Movement - genetics; Eicosanoic Acids - metabolism; Heat shock proteins; Hep G2 Cells; Hepatocellular carcinoma; hepatoma; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Humans; Hydroxyeicosatetraenoic Acids - pharmacology; Inhibitors; Invasion; Kinases; lipoxygenase; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; metastasis; neoplasm cells; Neoplasm Invasiveness; Pathways; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Progressions; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; small interfering RNA; Tumors; 15-LO-1; Hsp90; SD; 13-HODE; 15-Lipoxygenase-1; HCC; 15-HETE; Hepatocellular carcinoma; 15-Hydroxyeicosatetraenoic acid; Invasion; Apoptosis
• ISSN: 1357-2725; 1878-5875; 1878-5875
• DOI: 10.1016/j.biocel.2013.02.018

•15-LO-1 activation is required for the survival in liver carcinoma cells.•The promotive effects of hypoxia on HCC cells are mediated by 15-LO-1/15-HETE.•The anti-apoptotic effects of 15-HETE are mediated by PI3K/Akt/Hsp90 in HCC cells.•15-HETE promoted the migration and invasion of HCC cells via PI3K/Akt/Hsp90.•15-HETE stimulates Akt interation with Hsp90 in HCC cells. 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 Akt 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 Akt with heat shock protein 90, and suggest a new therapeutic target for hepatocellular carcinoma.