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

Oncogene volume 28, pages 2581–2592 (2009)Cite this article

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-1α-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.

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Abbreviations

CCCP:

carbonylcyanide m-chlorophenylhydrazone

CDDP:

cisplatin

dnPim-1:

dominant-negative Pim-1

HIF-1:

hypoxia-inducible factor-1

HRE:

hypoxia response element

MTP:

mitochondrial transmembrane potential

TMRE:

tetramethylrhodamine, ethylester, perchlorate

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Acknowledgements

This work was supported in part by the NIHRO1CA (089266 Lee MH), Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) (Chen J), Grants-in-Aid for Cancer Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (Kobayashi M), US Department of Defense Breast Cancer Research Program of the Office of the Congressionally Directed Medical Research Programs (DOD SIDA BC062166 Yeung SJ & Lee MH) and Cancer Center Core Grant (CA16672). We thank Dr BQ Vuong for providing the pCDNA3.1-His-SOCS1 plasmid. We thank Mrs Shirley Ware-Gully for her assistance in preparing the article.

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Author notes

  1. M Kobayashi

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

Authors and Affiliations

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

    J Chen, S Darmanin & Y Qiao

  2. Department of Surgical Oncology, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan

    J Chen

  3. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Chen, Y Qiao, C Gully, R Zhao & M H Lee

  4. Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

    M Kobayashi

  5. Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S C Yeung

  6. Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S C Yeung

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Correspondence to S C Yeung or M H Lee.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Chen, J., Kobayashi, M., Darmanin, S. et al. Pim-1 plays a pivotal role in hypoxia-induced chemoresistance. Oncogene 28, 2581–2592 (2009). https://doi.org/10.1038/onc.2009.124

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