title: ETS-1: A potential target of glycolysis for metabolic therapy by regulating glucose metabolism in pancreatic cancer.
abstract: Pancreatic cancer is one of the most lethal malignancies of all types of cancer due to lack of early symptoms and its resistance to conventional therapy. In our previous study, we have shown that v‑ets erythroblastosis virus E26 oncogene homolog‑1 (ETS‑1) promote cell migration and invasion in pancreatic cancer cells. However, the function of ETS‑1 in regulation of glycolysis and autophagy during progression of pancreatic cancer has not been defined yet. In this study, we sought to identify the potential role for silencing ETS‑1 in reducing the expression of glucose transporter‑1 (GLUT‑1) to disturb glycolysis through alteration of 'Warburg effect', by which could result in AMP‑activated protein kinase (AMPK) activation, autophagy induction and reduction of cell viability. MTT assay was applied to assess the cell viability in ETS‑1 silencing cells and control groups. Glucose absorption rate, lactate production rate and cellular ATP level were measured by standard colorimetric assay kits. The levels of mRNAs of ETS‑1, GLUT‑1, autophagy‑related gene 5 (ATG5) and ATG7 were analyzed by qRT‑PCR. The expression of ETS‑1, GLUT‑1, ATG5, ATG7, p‑AMPK, and LC3II proteins were evaluated by western blot analysis. GraphPad Prism 5.0 was used for all statistical analysis. We found that cell viability was obviously attenuated after silencing ETS‑1. Besides, our results also showed that the expression of GLUT‑1 significantly declined in ETS‑1 silencing cell lines which resulted in a lower glucose utilization and lactate production. Furthermore, the inhibition of glycolysis, which depends on glucose utilization and lactate production, reduced the generation of energy in the form of ATP. Moreover, the reduction of cellular ATP was associated with stimulation of AMP‑activated protein kinase (AMPK) and induction of autophagy. Our results indicated that ETS‑1 induced autophagy after inhibition of glycolysis, and thus led to comparative decrease of cell viability. These results implied that ETS‑1 could be a potential target for tumor metabolic therapy.
authors.affiliation: Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China.
authors.forename: Xiu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Jiangyin People's Hospital, Jiangyin, Jiangsu 224000, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China.
authors.forename: Mohanad
authors.initials: M
authors.lastname: Aldarouish
authors.affiliation: Department of Oncology, Binhai People's Hospital, Yancheng, Jiangsu 224500, P.R. China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Yin
authors.affiliation: Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China.
authors.forename: Cailian
authors.initials: C
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D000255:Adenosine Triphosphate / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D053858:Metabolic Networks and Pathways; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050784:Proto-Oncogene Protein c-ets-1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C494041:ETS1 protein, human; D009363:Neoplasm Proteins; D050784:Proto-Oncogene Protein c-ets-1; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D005947:Glucose