Journal
ONCOGENE
Volume 28, Issue 28, Pages 2581-2592Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2009.124
Keywords
Pim-1; hypoxia; apoptosis; chemoresistance; mitochondrial transmembrane potential
Funding
- NIHRO1CA [089266]
- Japan Society for the Promotion of Science (JSPS)
- Japanese Ministry of Education, Culture, Sports, Science and Technology
- US Department of Defense Breast Cancer Research Program of the Office of the Congressionally Directed Medical Research Programs [DOD SIDA BC062166]
- Cancer Center Core [CA16672]
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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-1 alpha-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. Oncogene (2009) 28, 2581-2592; doi: 10.1038/onc.2009.124; published online 1 June 2009
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