Hypoxic induction of HIF-1alpha and VEGF expression in head and neck squamous cell carcinoma lines is mediated by stress activated protein kinases

Babak Shemirani, David L Crowe
Oral Oncology 2002, 38 (3): 251-7
Solid tumors must establish a blood supply in order to proliferate and grow. Cancer cells secrete soluble factors which can induce proliferation and migration of capillary endothelial cells. Among the most potent of the angiogenic factors is vascular endothelial growth factor (VEGF). Increased VEGF expression by malignant tumors has been associated with high vascularity, increased cancer cell growth, and lymph node metastasis. Reduced oxygen tension has been shown to increase VEGF production by induction of the transcription factor hypoxia inducible factor 1 alpha (HIF-1alpha). The mechanisms by which hypoxic tumor environments induce HIF-1alpha and VEGF expression are largely unknown. Jun N terminal kinase (JNK1) and p38 kinase are activated by a variety of stress stimuli. To determine if hypoxic activation of these stress activated protein kinases regulated HIF-1alpha and VEGF expression, we assayed JNK1 and p38 activity in squamous cell carcinoma (SCC) lines grown under normoxic or hypoxic conditions. Hypoxia rapidly induced both JNK1 and p38 activity in these cells. This activation correlated with induction of HIF-1alpha expression and DNA binding activity which was blocked by the p38 inhibitor SB203580. Hypoxia also increased VEGF production by SCC lines, which was inhibited by treatment with SB203580. Overexpression of JNK1 or p38 was sufficient to induce HIF-1alpha and VEGF expression. These results indicate that induction of SAPKs by hypoxia regulates HIF-1alpha and VEGF expression in head and neck carcinoma cell lines.

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