title: Extracellular superoxide dismutase suppresses hypoxia-inducible factor-1α in pancreatic cancer.
abstract: Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that governs cellular responses to reduced oxygen availability by mediating crucial homeostatic processes and is a major survival determinant for tumor cells growing in a low-oxygen environment. Clinically, HIF-1α seems to be important in pancreatic cancer, as HIF-1α correlates with metastatic status of the tumor. Extracellular superoxide dismutase (EcSOD) inhibits pancreatic cancer cell growth by scavenging nonmitochondrial superoxide. We hypothesized that EcSOD overexpression leads to changes in the O2(-)/H2O2 balance modulating the redox status affecting signal transduction pathways. Both transient and stable overexpression of EcSOD suppressed the hypoxic accumulation of HIF-1α in human pancreatic cancer cells. This suppression of HIF-1α had a strong inverse correlation with levels of EcSOD protein. Coexpression of the hydrogen peroxide-removing protein glutathione peroxidase did not prevent the EcSOD-induced suppression of HIF-1α, suggesting that the degradation of HIF-1α observed with high EcSOD overexpression is possibly due to a low steady-state level of superoxide. Hypoxic induction of vascular endothelial growth factor (VEGF) was also suppressed with increased EcSOD. Intratumoral injections of an adenoviral vector containing the EcSOD gene into preestablished pancreatic tumors suppressed both VEGF levels and tumor growth. These results demonstrate that the transcription factor HIF-1α and its important gene target VEGF can be modulated by the antioxidant enzyme EcSOD.
authors: Department of Surgery, The University of Iowa College of Medicine, Iowa City, IA 52242, USA.
authors: Zita A
authors: ZA
authors: Sibenaller
authors: Department of Surgery, The University of Iowa College of Medicine, Iowa City, IA 52242, USA.
authors: Jessemae L
authors: JL
authors: Welsh
authors: Department of Radiation Oncology, The University of Iowa College of Medicine, Iowa City, IA 52242, USA.
authors: Changbin
authors: C
authors: Du
authors: Department of Radiation Oncology, The University of Iowa College of Medicine, Iowa City, IA 52242, USA.
authors: Jordan R
authors: JR
authors: Witmer
authors: Department of Radiation Oncology, The University of Iowa College of Medicine, Iowa City, IA 52242, USA.
authors: Hannah E
authors: HE
authors: Schrock
authors: Department of Radiation Oncology, The University of Iowa College of Medicine, Iowa City, IA 52242, USA.
authors: Juan
authors: J
authors: Du
authors: Department of Radiation Oncology, The University of Iowa College of Medicine, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA.
authors: Garry R
authors: GR
authors: Buettner
authors: Department of Radiation Oncology, The University of Iowa College of Medicine, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA.
authors: Prabhat C
authors: PC
authors: Goswami
authors: Department of Radiation Oncology, The University of Iowa College of Medicine, Iowa City, IA 52242, USA.
authors: John A
authors: JA
authors: Cieslak
authors: Department of Surgery, The University of Iowa College of Medicine, Iowa City, IA 52242, USA; Department of Radiation Oncology, The University of Iowa College of Medicine, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA; Veterans Affairs Medical Center, Iowa City, IA 52242, USA. Electronic address: joseph-cullen@uiowa.edu.
authors: Joseph J
authors: JJ
authors: Cullen
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005979:Glutathione Peroxidase / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; C405619:HIGD1A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D042461:Vascular Endothelial Growth Factor A; D013481:Superoxides; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase
keywords: Extracellular superoxide dismutase; Free radicals; Hypoxia-inducible factor; Pancreatic cancer; Superoxide