Hypoxia Inducible Factor-1 Mediates Effects of Insulin on Pancreatic Cancer Cells and Disturbs Host Energy Homeostasis

• Published in: The American journal of pathology Vol. 170; no. 2; pp. 469 - 477
• Main Authors: Wang, Feng, Li, Shu Shun, Segersvärd, Ralf, Strömmer, Lisa, Sundqvist, Karl-Gösta, Holgersson, Jan, Permert, Johan
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01-02-2007; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Biological and medical sciences; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation - drug effects; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation - drug effects; Glycolysis - drug effects; Hexokinase - biosynthesis; Homeostasis - drug effects; Humans; Hypoglycemic Agents - metabolism; Hypoglycemic Agents - pharmacology; Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis; Insulin - metabolism; Insulin - pharmacology; Investigative techniques, diagnostic techniques (general aspects); Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms - metabolism; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Regular; Tumors; Vascular Endothelial Growth Factor A - biosynthesis; Pancreatic hormone; Anatomic pathology; Energy; Pancreas cancer; Homeostasis; Digestive diseases; Transcription factor HIF1; Host; Malignant tumor; Insulin; Tumor cell; Pancreatic disease
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2007.060489

Intratumoral hypoxia and paracrine insulin stimulate the expression of hypoxia inducible factor-1α (HIF-1α) in pancreatic cancer cells. In the present studies, we investigated whether insulin-induced HIF-1α expression is a prerequisite for insulin to induce other trophic effects in MiaPaCa2 human pancreatic cancer cells and whether inhibition of HIF-1α expression would decrease tumor glycolysis and improve host energy homeostasis. We found that hypoxia was a prerequisite for induction of HIF-1α 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-1α and therefore lacked HIF-1α protein. This suggests that HIF-1α 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-1α helps sustain pancreatic cancer cells and disturbs host energy homeostasis.