Inhibition Of IRE1/XBP1 Enhanced Akt Inhibitors MK-2206 The Role Of Treat With Esophageal Squamous Carcinoma

Esophageal Cancer is a common occurrence in the esophageal epithelium of the digestive tract malignant tumor,including squamous carcinoma and ade nocarcinoma.The number of esophageal cancer in China more than anywhere el se in the world.Esophageal cancer patients with no obvious symptoms in the early days more,chemotherapy usually used for terminal-stage treatment.Howe ver,the current chemotherapy drugs have a few shortcomings include selective low and drug resistance.It is difficult to satisfy the need of clinical treatment of esophageal cancer.Molecular targeted therapy for esophageal cancer treatm ent brings hope,discovery of new therapeutic targets,looking for novel targete d drugs and drug use,that is the important direction of the esophageal cancer research.Akt(Protein Kinase B)in esophageal cancer cell line an-d esophageal tumo r tissues are unusually over expression,so choose the clinical of Akt targeted small molecule inhibitors of MK-2206 for restrain the growth of the esophagea l cancer cells has a key role.Previous studies found in MK-2206 for esophage al squamous carcinoma P53 mutations Kyse450 and Kyse510 antitumor activity are poorer,suggesting that other mechanisms in affect the sensitivity of the MK-2206 for two cells: such as endoplasmic reticulum stress.Therefore,the pur pose of this paper is to research for the MK-2206 effect of esophageal cancer cells by endoplasmic reticulum stress and the inhibition of endoplasmic reticulu m stress pathway can enhance MK-2206 sensitivity to Kyse450 and Kyse510.This paper mainly studies the following several aspects:(1)CCK8 is used to analysis of MK-2206 treat with five esophageal squa mous cancer cells cell proliferation inhibitions,selected two drug resistances es ophageal cancer cell lines as the main research objective of this paper.(2)Using flow cytometry and Western blot to detect MK-2206 influenced with cell apoptosis,cell cycle and Akt pathway for drug resistance esophagealcancer.Using Western blot to detect MK-2206 for the effects of endoplasmic re ticulum stress pathway.(3)SiRNA interference XBP1,and use of IRE1 endonuclease inhibition of STF-083010 influence on antitumor activity of the MK-2206;Combination STF-083010 and MK-2206 influenced with two drug resistances of cell apoptosis,cell autophagy,cell cycle and in vivo transplantation tumor,explore the mechani sm.The results show that:(1)MK-2206 has poorly antitumor activity for esophageal cancer P53 mutat ions cell lines Kyse450 and Kyse510,It does not cause two drug resistance of esophageal cancer cells apoptosis;Two drug resistance esophageal cancer cell c ycle arrest in G0/G1 phase;MK-2206 can inhibit the activation of Akt.(2)MK-2206 can cause one of endoplasmic reticulum stress pathway IRE1/XBP1 activation;IRE1 endonuclease inhibitors STF-083010 and MK-2206 combination can significantly inhibit the proliferation of tumor cells;Enhance the autophagy induced by MK-2206 on esophageal cancer cell,;Tumor cell cycle arrest in G0/G1 phase,to strengthen the P21 cycle control,but had no signific ant effect on apoptosis,combination with MK-2206 and STF-083010 can cause the increase of IRE1,but STF-083010 can inhibit IRE1 activation of XBP1,a nd affect IRE1 and Akt protein interactions.(3)STF-083010 combination MK-2206 enhanced antitumor activity in vivo,inducing transplantation tumor cell necrosis.Conclusion: The inhibition of IRE1/XBP1 pathways can significantly enhan ce the MK-2206 on esophageal Kyse450 and Kyse510 antitumor activity in viv o and in vitro,by causing cell autophagy,and enhance the P21 for cycle regul ation function.