title: Hypoxia-inducible factor 1 promotes chemoresistance of lung cancer by inducing carbonic anhydrase IX expression.
abstract: Lung cancer treatment is difficult owing to chemoresistance. Hypoxia-inducible factor 1 (HIF-1) and HIF-1-induced glycolysis are correlated with chemoresistance; however, this is not evident in lung cancer. We investigated the effect of HIF-1α and carbonic anhydrase IX (CAIX), a transmembrane protein neutralizing intracellular acidosis, on chemoresistance and prognosis of lung cancer patients after induction chemoradiotherapy. Associations of HIF-1α, glucose transporter 1 (GLUT1), and CAIX with chemoresistance of lung cancer were investigated using A549 lung cancer cells under normoxia or hypoxia in vitro. HIF-1α-induced reprogramming of glucose metabolic pathway in A549 cells and the effects of HIF-1 and CAIX on the cytotoxicity of vinorelbine were investigated. Immunohistochemical analyses were performed to determine HIF-1α, GLUT1, and CAIX expression levels in cancer specimens from lung cancer patients after induction chemoradiotherapy. Hypoxia induced HIF-1α expression in A549 cells. Moreover, hypoxia induced GLUT1 and CAIX expression in A549 cells in a HIF-1-dependent manner. Glucose metabolic pathway was shifted from oxidative phosphorylation to glycolysis by inducing HIF-1α in A549 cells. HIF-1 and CAIX induced chemoresistance under hypoxia, and their inhibition restored the chemosensitivity of A549 cells. The expression levels of HIF-1α, GLUT1, and CAIX were associated with poor overall survival of lung cancer patients after induction chemoradiotherapy. HIF-1 and CAIX affected the chemosensitivity of A549 cells and prognosis of lung cancer patients. Therefore, inhibition of HIF-1 and CAIX might improve prognosis of lung cancer patients after induction chemoradiotherapy. Further analysis might be helpful in developing therapies for lung cancer.
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Terumasa
authors.initials: T
authors.lastname: Sowa
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Toshi
authors.initials: T
authors.lastname: Menju
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Toyofumi F
authors.initials: TF
authors.lastname: Chen-Yoshikawa
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Nishikawa
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Shikuma
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Motoyama
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hijiya
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Aoyama
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sonobe
authors.affiliation: Laboratory of Cancer Cell Biology, Radiation Biology Center, Kyoto University, Yoshida Konoecho, Sakyo-ku, Kyoto, 606-8501, Japan.|Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Saitama, 332-0012, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
mesh_terms: D000072283:A549 Cells; D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX / Q000378:metabolism*; D015687:Cell Hypoxia; D059248:Chemoradiotherapy; D019008:Drug Resistance, Neoplasm; D005260:Female; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000077235:Vinorelbine
chemical_list: D000951:Antigens, Neoplasm; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495677:SLC2A1 protein, human; D014747:Vinblastine; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D000077235:Vinorelbine
keywords: Carbonic anhydrase IX; chemoresistance; hypoxia-inducible factor 1; induction chemoradiotherapy; lung cancer