1. ¹Division of Cancer-Related Genes, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
2. ²Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan
3. ³Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4. ⁴Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
5. ⁵Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
6. ⁶Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence: Dr MH Lee, Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Box 79, 1515 Holcombe Blvd., Houston, TX 77030, USA. E-mail: mhlee@mdanderson.org; Dr S-CJ Yeung, The University of Texas MD Anderson Cancer Center, Box 1465, 1515 Holcombe Blvd., Houston, TX 77030, USA. E-mail: syeung@mdanderson.org

⁷Current address: School of Nursing and Social Services, Health Science University of Hokkaido, Sapporo, Japan.

Received 9 October 2008; Revised 21 April 2009; Accepted 26 April 2009; Published online 1 June 2009.

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-1-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.