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(American Journal of Pathology. 2007;170:469-477.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060489

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

Feng Wang^*, Shu Shun Li, Ralf Segersvärd^*, Lisa Strömmer^*, Karl-Gösta Sundqvist, Jan Holgersson and Johan Permert^*

From the Departments of Surgery^* and Clinical Immunology, Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden

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

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