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Hypoxia Inducible Factor-1 Mediates Effects of Insulin on Pancreatic Cancer Cells and Disturbs Host Energy Homeostasis
- Source :
- The American Journal of Pathology. 170:469-477
- Publication Year :
- 2007
- Publisher :
- Elsevier BV, 2007.
-
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.
- Subjects :
- Vascular Endothelial Growth Factor A
medicine.medical_specialty
Pancreatic disease
medicine.medical_treatment
Mice, Nude
Biology
Pathology and Forensic Medicine
Mice
Paracrine signalling
chemistry.chemical_compound
Cell Line, Tumor
Hexokinase
Internal medicine
Pancreatic cancer
medicine
Animals
Homeostasis
Humans
Hypoglycemic Agents
Insulin
Cell Proliferation
Hypoxia-Inducible Factor 1, alpha Subunit
medicine.disease
Cell Hypoxia
Cell biology
Pancreatic Neoplasms
Vascular endothelial growth factor A
medicine.anatomical_structure
Endocrinology
Gene Expression Regulation
chemistry
Pancreas
Glycolysis
Neoplasm Transplantation
Regular Articles
Subjects
Details
- ISSN :
- 00029440
- Volume :
- 170
- Database :
- OpenAIRE
- Journal :
- The American Journal of Pathology
- Accession number :
- edsair.doi.dedup.....7eacdd9cf823408093fe131f63f5ce7e