ABSTRACT
Purpose: Hypoxia-inducible factor-2α (HIF2α) is regarded as a preferential target for individualized hepatocellular carcinoma (HCC) treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF2α activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF2α activity and of sorafenib resistance in hypoxic HCC cells.Experimental Design: The cell viability, migration, and invasion abilities were measured to analyze the effects of HIF2α on hypoxic HCC cells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF2α level and activity, which then reduces the sensitivity of sorafenib treatment in hypoxic HCC cells.Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF2α and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF2α activity by promoting HIF2α nuclear translocation via MAPK pathway. The activation of HIF2α then led to the enhanced activation of VEGF, cyclin D1, and TGFα/EGFR pathway to mediate HCC development and reduce the sensitivity of sorafenib. More importantly, COX-2-specific inhibitors synergistically enhanced the antitumor activity of sorafenib treatment.Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF2α expression and activity to promote HCC development and reduce sorafenib sensitivity by constitutively activating the TGFα/EGFR pathway. This study highlights the potential of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment. Clin Cancer Res; 24(13); 3204-16. ©2018 AACR.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Cyclooxygenase 2/metabolism , Dinoprostone/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Sorafenib/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Survival/drug effects , Cyclin D1/metabolism , Disease Models, Animal , Drug Resistance, Neoplasm , Humans , Hypoxia/metabolism , Liver Neoplasms/pathology , Mice , Neovascularization, Pathologic/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proteolysis , Signal Transduction/drug effects , Sorafenib/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: To study the effect of puerarin on the expression of Hsp (heat shock protein) 70 in the rats with cerebral injury induced by acute local ischemia. METHOD: Rat model of acute local cerebral ischemia was made by ligating middle cerebral artery. The Hsp70 expression in brain tissue was detected by SP method of immunohistochemistry. RESULT: The expression of Hsp70 was significantly higher in puerarintreated rats than those in the rats with cerebral ischemia. CONCLUSION: Puerarin can enhance the level of Hsp70 expression in the rats with cerebral injury induced by acute local ischemia.
Subject(s)
Brain Ischemia/metabolism , HSP70 Heat-Shock Proteins/metabolism , Isoflavones/pharmacology , Neuroprotective Agents/pharmacology , Pueraria , Animals , Brain Ischemia/etiology , Brain Ischemia/pathology , Female , Infarction, Middle Cerebral Artery/complications , Isoflavones/isolation & purification , Male , Neurons/metabolism , Neuroprotective Agents/isolation & purification , Plants, Medicinal/chemistry , Pueraria/chemistry , Rats , Rats, WistarABSTRACT
OBJECTIVE: To study the protection of puerarin on the cerebral injury in the rats with acute local ischemia. METHOD: Rat was evaluated model of acute local cerebral ischemia was made by ligating middle cerebral artery. The cerebral damage toxylin and eosin((HE). RESULT: The number of died neurons were significantly less in puerarin-treated rats than in the rats with cerebral ischemia (P < 0. 05). Similarly, the cerebral edema were significantly attenuated in the puerarin-treated rats as compared with cerebrally ischemic rats. CONCLUSION: Puerarin can prevent the neuron from damage induced by acute cerebral ischemia.