Signal pathway of hypoxia-inducible factor-1α phosphorylation and its interaction with von Hippel-Lindau tumor suppressor protein during ischemia in MiaPaCa-2 pancreatic cancer cells

Purpose and Experimental Design: Previously, we observed that the activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK1) is mediated through the activation of apoptosis signal - regulating kinase 1 (ASK1) as a result of the reactive oxygen species -mediated dissociation of glutaredoxin and thioredoxin from ASK1. In this study, we examined whether p38 MAPK and JNK1 are involved in the accumulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) during ischemia. Human pancreatic cancer MiaPaCa-2 cells were exposed to low glucose (0.1 mmol/L) with hypoxia (0.1% O-2). Results and Conclusions: During ischemia, p38 MAPK and JNK1 were activated in Mia PaCa-2 pancreatic cancer cells. The activated p38 MAPK, but not JNK1, phosphorylated HIF-1 alpha. Data from in vivo binding assay of von Hippel-Lindau tumor suppressor protein with HIF-1 alpha( suggests that the p38-mediated phosphorylation of HIF-1 alpha contributed to the inhibition of HIF-1 alpha and von Hippel-Linclau tumor suppressor protein interaction during ischemia. S13203580, a specific inhibitor of p38 MAPK, inhibited HIF-1 alpha accumulation during ischemia, probably resulting from the ubiquitination and degradation of HIF-1 alpha.