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Deletion of Pim kinases elevates the cellular levels of reactive oxygen species and sensitizes to K-Ras-induced cell killing

Oncogene volume 34, pages 3728–3736 (2015)Cite this article

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Abstract

The Pim protein kinases contribute to transformation by enhancing the activity of oncogenic Myc and Ras, which drives significant metabolic changes during tumorigenesis. In this report, we demonstrate that mouse embryo fibroblasts (MEFs) lacking all three isoforms of Pim protein kinases, triple knockout (TKO), cannot tolerate the expression of activated K-Ras (K-RasG12V) and undergo cell death. Transduction of K-RasG12V into these cells markedly increased the level of cellular reactive oxygen species (ROS). The addition of N-acetyl cysteine attenuated ROS production and reversed the cytotoxic effects of K-RasG12V in the TKO MEFs. The altered cellular redox state caused by the loss of Pim occurred as a result of lower levels of metabolic intermediates in the glycolytic and pentose phosphate pathways as well as abnormal mitochondrial oxidative phosphorylation. TKO MEFs exhibit reduced levels of superoxide dismutase (Sod), glutathione peroxidase 4 (Gpx4) and peroxiredoxin 3 (Prdx3) that render them susceptible to killing by K-RasG12V-mediated ROS production. In contrast, the transduction of c-Myc into TKO cells can overcome the lack of Pim protein kinases by regulating cellular metabolism and Sod2. In the absence of the Pim kinases, c-Myc transduction permitted K-RasG12V-induced cell growth by decreasing Ras-induced cellular ROS levels. These results demonstrate that the Pim protein kinases have an important role in regulating cellular redox, metabolism and K-Ras-stimulated cell growth.

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Acknowledgements

This work was supported in part by the Genomics Shared Resource at Hollings Cancer Center and Seahorse Biosciences Academic Core Facility, Medical University of South Carolina. We thank Dr Allen J Ebens at Genentech Inc. and Novartis Oncology for providing the Pim kinase inhibitors used in this study. This work was supported by the NIH P30-CA138313, DOD W81XWH-08-PCRP-IDA, R01 CA1732000, and American Cancer Society Institutional Research Grant awarded to the Hollings Cancer Center, Medical University of South Carolina.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA,

    J H Song

  2. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA,

    J H Song, S Chatterjee, E Kistner-Griffin, S Mahajan, S Mehrotra & A S Kraft

  3. Department of Medicine, Medical University of South Carolina, Charleston, SC, USA,

    N An & A S Kraft

  4. Department of Surgery, Medical University of South Carolina, Charleston, SC, USA,

    S Chatterjee & S Mehrotra

  5. Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA

    E Kistner-Griffin

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Correspondence to J H Song or A S Kraft.

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Song, J., An, N., Chatterjee, S. et al. Deletion of Pim kinases elevates the cellular levels of reactive oxygen species and sensitizes to K-Ras-induced cell killing. Oncogene 34, 3728–3736 (2015). https://doi.org/10.1038/onc.2014.306

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