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Hypoxia-inducible factor 1α triggers growth hormone synthesis in somatotrophinoma cells
The survival and growth of solid tumors is greatly dependent upon adaptations which not only favor the continued proliferation of neoplastic cells themselves, but also their surrounding microenvironment. One of the most pivotal challenges solid tumors face is the inevitable decrease in oxygen delivery resulting from the outgrowth of proliferating cells beyond the extension of their original blood supply. Adaptive processes which allow tumor cells to survive under hypoxic conditions include the production of growth factors such as vascular endothelial growth factor (VEGF), which trigger the sprouting of new vessels into the tumor mass. We found that acromegalic tumors have low CD31 immunoreactivity scores, indicating low vascularization, but present with high VEGF-A secretion. VEGF-A expression is transcriptionally regulated by the hypoxia-inducible-factor 1a (HIF1a). HIF1a expression is increased in acromegalic tumors compared to the normal pituitary. HIF1a overexpression in the GH3 somatotrophinoma cell line increased growth hormone secretion and promoter activity. GH transcription is under the positive control of the cAMP cascade. HIF1a and maintained forskolin-induced CREB phosphorylation by blocking its attenuation and increased cAMP responsive element (CRE) transcriptional activity, as measured by luciferase promoter assay. The phosphorylation status of CREB is negatively regulated by the protein-phosphatase 1(PP1). Phosphatase activity in HIF1a overexpressing GH3 cells was measured and showed no significant increase compared to control cells indicating that HIF1a affects CREB transcriptional activity independently of PP1 activity.
Taken together, our results demonstrate that the overexpression of HIF1a as it can be found in human acromegalic tumors exerts important influences on growth hormone regulation. Therefore, HIF1a may pose an interesting target which may help sensitize acromegalic tumor cells to pharmacological therapy.