• Sung Youl Kim and Jeen-Woo Park.
• School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Taegu 702-701, Republic of Korea.
• Biochimie. 2010 Dec 1; 92 (12): 1908-13.

AbstractThe transcription factor hypoxia-inducible factor-1 (HIF-1) is an important regulator of the tumor response to hypoxia, including increased angiogenesis, glycolytic metabolism, and resistance to apoptosis. In the current study, small interfering RNA (siRNA)-mediated knockdown of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDPm) suppressed hypoxia-induced stimulation of HIF-1α protein expression in PC3 human prostate cancer cells. Treatment with the 26S proteasome inhibitor MG132 failed to abrogate the suppression of HIF-1α accumulation induced by IDPm knockdown, whereas HIF-1α levels were reduced by cycloheximide treatment in both control and IDPm siRNA-transfected cells. These results suggested that the suppression of HIF-1α accumulation by IDPm knockdown in PC3 cells was due to an inhibition of HIF-1α transcription. Inactivation of the phosphoinsotide-3 kinase (PI3K)/Akt pathway decreased HIF-1α expression through inactivation of Sp1. Thus, IDPm siRNA functioned as a potentially useful agent for targeting chemo- and radio-resistant hypoxic cells within solid tumors through inhibition of HIF-1α expression.Copyright © 2010 Elsevier Masson SAS. All rights reserved.

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