title: Hypoxia regulates ABCG2 activity through the activivation of ERK1/2/HIF-1α and contributes to chemoresistance in pancreatic cancer cells.
abstract: Pancreatic cancer is a drug resistant hypovascular tumor. Although there are many studies on the mechanism of chemoresistance in pancreatic cancers, studies on the relationship between ABCG2 and chemoresistance during hypoxia of pancreatic cancer are rare. Hypoxia-inducible factor-1 (HIF-1α) is a master regulator of the transcriptional response to oxygen deprivation in cancer cells. The aim of this study was to examine the role of ABCG2 and HIF-1α in mediating chemoresistance during hypoxia in pancreatic cancer. In this study, we detected the expression levels of ABCG2, ERK/phosphorylated-ERK (p-ERK) and HIF-1α by immunohistochemistry in fresh pancreatic cancer and paracarcinoma tissues obtained from 25 patients. The mechanism by which p-ERK1/2 and HIF-1α affect ABCG2s expression was analyzed in the hypoxic cultured human pancreatic cancer cell line Capan-2. ABCG2-mediatedregulation of gemcitabine response under hypoxic conditions in pancreatic cancer cells was observed. It was found that ABCG2, ERK/p-ERK and HIF-1α were overexpressed in cancer tissues. ABCG2, HIF-1α and p-ERK levels were demonstrated to be high during hypoxic conditions in pancreatic cancer cells. Hypoxia induced phosphorylation of ERK1/2 to activate HIF-1α and contribute the ABCG2 expression and mediated gemcitabine chemoresistance in pancreatic cancer cells. Hypoxic conditions induced HIF-1α binding to target gene sequences in the ABCG2 promoter, resulting in increased transcription in pancreatic cancer cells. We demonstrated that hypoxia-induced chemoresistance is due to the regulation of ABCG2 through the activation of ERK1/2/HIF-1α. ABCG2 could serve as a predictor of gemcitabine response and, potentially, as a chemotherapeutic target in pancreatic cancer. Inhibition of ERK1/2 and HIF-1αcould result in increased gemcitabine sensitization in pancreatic cancer with highly expressed ABCG2 cell member protein.
authors.affiliation: a School of Medicine, Nankai University , Tianjin , China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: He
authors.affiliation: a School of Medicine, Nankai University , Tianjin , China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: b Tianjin Medical University Cancer Institute and Hospital , Tianjin , China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: a School of Medicine, Nankai University , Tianjin , China.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Shi
authors.affiliation: a School of Medicine, Nankai University , Tianjin , China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Xin
authors.affiliation: b Tianjin Medical University Cancer Institute and Hospital , Tianjin , China.
authors.forename: Ti
authors.initials: T
authors.lastname: Zhang
authors.affiliation: a School of Medicine, Nankai University , Tianjin , China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Shen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000096:biosynthesis* / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis* / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics; D000093542:Gemcitabine
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D003841:Deoxycytidine; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000093542:Gemcitabine
keywords: ABCG2; ERK; HIF-1α; chemoresistance; combine; hypoxia; pancreatic cancer