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Oncogene. 2009 Jul 16;28(28):2581-92. doi: 10.1038/onc.2009.124. Epub 2009 Jun 1.

Pim-1 plays a pivotal role in hypoxia-induced chemoresistance.

Author information

1
Division of Cancer-Related Genes, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.

Abstract

Hypoxia changes the responses of cancer cells to many chemotherapy agents, resulting in chemoresistance. The underlying molecular mechanism of hypoxia-induced drug resistance remains unclear. Pim-1 is a survival kinase, which phosphorylates Bad at serine 112 to antagonize drug-induced apoptosis. Here we show that hypoxia increases Pim-1 in a hypoxia-inducible factor-1alpha-independent manner. Inhibition of Pim-1 function by dominant-negative Pim-1 dramatically restores the drug sensitivity to apoptosis induced by chemotherapy under hypoxic conditions in both in vitro and in vivo tumor models. Introduction of siRNAs for Pim-1 also resensitizes cancer cells to chemotherapy drugs under hypoxic conditions, whereas forced overexpression of Pim-1 endows solid tumor cells with resistance to cisplatin, even under normoxia. Dominant-negative Pim-1 prevents a decrease in mitochondrial transmembrane potential in solid tumor cells, which is normally induced by cisplatin (CDDP), followed by the reduced activity of Caspase-3 and Caspase-9, indicating that Pim-1 participates in hypoxia-induced drug resistance through the stabilization of mitochondrial transmembrane potential. Our results demonstrate that Pim-1 is a pivotal regulator involved in hypoxia-induced chemoresistance. Targeting Pim-1 may improve the chemotherapeutic strategy for solid tumors.

PMID:
19483729
PMCID:
PMC3358117
DOI:
10.1038/onc.2009.124
[Indexed for MEDLINE]
Free PMC Article

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