title: Hypoxia inducible factor-1 mediates effects of insulin on pancreatic cancer cells and disturbs host energy homeostasis.
abstract: Intratumoral hypoxia and paracrine insulin stimulate the expression of hypoxia inducible factor-1alpha (HIF-1alpha) in pancreatic cancer cells. In the present studies, we investigated whether insulin-induced HIF-1alpha expression is a prerequisite for insulin to induce other trophic effects in MiaPaCa2 human pancreatic cancer cells and whether inhibition of HIF-1alpha expression would decrease tumor glycolysis and improve host energy homeostasis. We found that hypoxia was a prerequisite for induction of HIF-1alpha mRNA expression by insulin in MiaPaCa2 cells. Under hypoxic conditions, insulin stimulated glycolysis, cell proliferation, and the secretion of vascular endothelial growth factor in regular MiaPaCa2 cells but not in a MiaPaCa2 variant (si-MiaPaCa2) that expressed specific short interfering RNA for HIF-1alpha and therefore lacked HIF-1alpha protein. This suggests that HIF-1alpha expression is required for insulin to induce other trophic effects. When si-MiaPaCa2 cells were transplanted into the pancreas of athymic mice, they were less tumorigenic and expressed less hexokinase than regular MiaPaCa2 cells. Body weight gain was attenuated in mice hosting tumors composed of regular MiaPaCa2 but not si-MiaPaCa2 cells. These results suggest that an interaction between insulin and HIF-1alpha helps sustain pancreatic cancer cells and disturbs host energy homeostasis.
authors.affiliation: Department of Surgery, Karolinska University Hospital at Huddinge, 141 86 Stockholm, Sweden. feng.wang@ki.se
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Shu Shun
authors.initials: SS
authors.lastname: Li
authors.forename: Ralf
authors.initials: R
authors.lastname: Segersvärd
authors.forename: Lisa
authors.initials: L
authors.lastname: Strömmer
authors.forename: Karl-Gösta
authors.initials: KG
authors.lastname: Sundqvist
authors.forename: Jan
authors.initials: J
authors.lastname: Holgersson
authors.forename: Johan
authors.initials: J
authors.lastname: Permert
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects*; D006593:Hexokinase / Q000096:biosynthesis; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: C497442:HIF1A protein, human; D007004:Hypoglycemic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D042461:Vascular Endothelial Growth Factor A; D006593:Hexokinase