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

Abstract

Purpose and Experimental Design: Previously, we observed that the activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH 2-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-1α (HIF-1α) during ischemia. Human pancreatic cancer MiaPaCa-2 cells were exposed to low glucose (0.1 mmol/L) with hypoxia (0.1% O2). Results and Conclusions: During ischemia, p38 MAPK and JNK1 were activated in MiaPaCa-2 pancreatic cancer cells. The activated p38 MAPK, but not JNK1, phosphorylated HIF-1α. Data from in vivo binding assay of von Hippel-Lindau tumor suppressor protein with HIF-1α suggests that the p38-mediated phosphorylation of HIF-1α contributed to the inhibition of HIF-1α and von Hippel-Lindau tumor suppressor protein interaction during ischemia. SB203580, a specific inhibitor of p38 MAPK, inhibited HIF-1α accumulation during ischemia, probably resulting from the ubiquitination and degradation of HIF-1α. © 2005 American Association for Cancer Research.