title: 15-lipoxygenase-1/15-hydroxyeicosatetraenoic acid promotes hepatocellular cancer cells growth through protein kinase B and heat shock protein 90 complex activation.
abstract: 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.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University (Daqing), Daqing 163319, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhang
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Liu
authors.forename: Liuping
authors.initials: L
authors.lastname: Wei
authors.forename: Tingting
authors.initials: T
authors.lastname: Shen
authors.forename: Cui
authors.initials: C
authors.lastname: Ma
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Wang
authors.forename: Yingli
authors.initials: Y
authors.lastname: Chen
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics; D004537:Eicosanoic Acids / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D004537:Eicosanoic Acids; D018841:HSP90 Heat-Shock Proteins; D006893:Hydroxyeicosatetraenoic Acids; C073049:15-hydroxyeicosanoic acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt