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PIM kinases alter mitochondrial dynamics and chemosensitivity in lung cancer

Oncogene volume 39, pages 2597–2611 (2020)Cite this article

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Abstract

Resistance to chemotherapy represents a major obstacle to the successful treatment of non-small-cell lung cancer (NSCLC). The goal of this study was to determine how PIM kinases impact mitochondrial dynamics, ROS production, and response to chemotherapy in lung cancer. Live-cell imaging and microscopy were used to determine the effect of PIM loss or inhibition on mitochondrial phenotype and ROS. Inhibition of PIM kinases caused excessive mitochondrial fission and significant upregulation of mitochondrial superoxide, increasing intracellular ROS. Mechanistically, we define a signaling axis linking PIM1 to Drp1 and mitochondrial fission in lung cancer. PIM inhibition significantly increased the protein levels and mitochondrial localization of Drp1, causing marked fragmentation of mitochondria. An inverse correlation between PIM1 and Drp1 was confirmed in NSCLC patient samples. Inhibition of PIM sensitized NSCLC cells to chemotherapy and produced a synergistic antitumor response in vitro and in vivo. Immunohistochemistry and transmission electron microscopy verified that PIM inhibitors promote mitochondrial fission and apoptosis in vivo. These data improve our knowledge about how PIM1 regulates mitochondria and provide justification for combining PIM inhibition with chemotherapy in NSCLC.

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Fig. 1: PIM1 is upregulated in advanced lung cancer and predicts poor survival outcomes.
Fig. 2: PIM inhibition increases mitochondrial superoxide production and total cellular ROS.
Fig. 3: Loss of PIM induces mitochondrial fragmentation.
Fig. 4: PIM1 affects mitochondrial phenotype in a Drp1-dependent manner.
Fig. 5: PIM inhibition sensitizes lung cancer cells to chemotherapy by altering the mitochondrial phenotype.
Fig. 6: Combined treatment with PIM inhibitor and docetaxel displays synergistic antitumor effects in vivo.

References

  1. Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res. 2016;5:288–300.

    Article  CAS  Google Scholar 

  2. Lin JJ, Shaw AT. Resisting resistance: targeted therapies in lung cancer. Trends Cancer. 2016;2:350–64.

    Article  Google Scholar 

  3. Joseph B, Ekedahl J, Sirzen F, Lewensohn R, Zhivotovsky B. Differences in expression of pro-caspases in small cell and non-small cell lung carcinoma. Biochem Biophys Res Commun. 1999;262:381–7.

    Article  CAS  Google Scholar 

  4. Li X, You M, Liu YJ, Ma L, Jin PP, Zhou R, et al. Reversal of the apoptotic resistance of non-small-cell lung carcinoma towards TRAIL by natural product toosendanin. Sci Rep. 2017;7:42748.

    Article  CAS  Google Scholar 

  5. Zhao J, Zhang J, Yu M, Xie Y, Huang Y, Wolff DW, et al. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene. 2013;32:4814–24.

    Article  CAS  Google Scholar 

  6. Xie LL, Shi F, Tan Z, Li Y, Bode AM, Cao Y. Mitochondrial network structure homeostasis and cell death. Cancer Sci. 2018;109:3686–94.

    Article  CAS  Google Scholar 

  7. Kong B, Wang Q, Fung E, Xue K, Tsang BK. p53 is required for cisplatin-induced processing of the mitochondrial fusion protein L-Opa1 that is mediated by the mitochondrial metallopeptidase Oma1 in gynecologic cancers. J Biol Chem. 2014;289:27134–45.

    Article  CAS  Google Scholar 

  8. Trotta AP, Chipuk JE. Mitochondrial dynamics as regulators of cancer biology. Cell Mol Life Sci. 2017;74:1999–2017.

    Article  CAS  Google Scholar 

  9. Kashatus JA, Nascimento A, Myers LJ, Sher A, Byrne FL, Hoehn KL, et al. Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell. 2015;57:537–51.

    Article  CAS  Google Scholar 

  10. Jezek J, Cooper KF, Strich R. Reactive oxygen species and mitochondrial dynamics: the Yin and Yang of mitochondrial dysfunction and cancer progression. Antioxidants (Basel). 2018;7:13.

  11. von Eyss B, Jaenicke LA, Kortlever RM, Royla N, Wiese KE, Letschert S, et al. A MYC-driven change in mitochondrial dynamics limits YAP/TAZ function in mammary epithelial cells and breast cancer. Cancer Cell. 2015;28:743–57.

    Article  Google Scholar 

  12. Qian W, Wang J, Roginskaya V, McDermott LA, Edwards RP, Stolz DB, et al. Novel combination of mitochondrial division inhibitor 1 (mdivi-1) and platinum agents produces synergistic pro-apoptotic effect in drug resistant tumor cells. Oncotarget. 2014;5:4180–94.

    Article  Google Scholar 

  13. Breckenridge DG, Stojanovic M, Marcellus RC, Shore GC. Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. J Cell Biol. 2003;160:1115–27.

    Article  CAS  Google Scholar 

  14. Estaquier J, Arnoult D. Inhibiting Drp1-mediated mitochondrial fission selectively prevents the release of cytochrome c during apoptosis. Cell Death Differ. 2007;14:1086–94.

    Article  CAS  Google Scholar 

  15. Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, et al. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell. 2001;1:515–25.

    Article  CAS  Google Scholar 

  16. Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell. 2004;15:5001–11.

    Article  CAS  Google Scholar 

  17. Thomas KJ, Jacobson MR. Defects in mitochondrial fission protein dynamin-related protein 1 are linked to apoptotic resistance and autophagy in a lung cancer model. PLoS ONE. 2012;7:e45319.

    Article  CAS  Google Scholar 

  18. Roberts ER, Thomas KJ. The role of mitochondria in the development and progression of lung cancer. Comput Struct Biotechnol J. 2013;6:e201303019.

    Article  Google Scholar 

  19. Cao L, Wang F, Li S, Wang X, Huang D, Jiang R. PIM1 kinase promotes cell proliferation, metastasis and tumor growth of lung adenocarcinoma by potentiating the c-MET signaling pathway. Cancer Lett. 2019;444:116–26.

    Article  CAS  Google Scholar 

  20. Warfel NA, Sainz AG, Song JH, Kraft AS. PIM kinase inhibitors kill hypoxic tumor cells by reducing Nrf2 signaling and increasing reactive oxygen species. Mol Cancer Ther. 2016;15:1637–47.

    Article  CAS  Google Scholar 

  21. Song JH, Padi SK, Luevano LA, Minden MD, DeAngelo DJ, Hardiman G, et al. Insulin receptor substrate 1 is a substrate of the Pim protein kinases. Oncotarget. 2016;20152–65.

  22. Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J. Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci USA. 2011;108:10190–5.

    Article  CAS  Google Scholar 

  23. Bordt EA, Clerc P, Roelofs BA, Saladino AJ, Tretter L, Adam-Vizi V, et al. The putative Drp1 inhibitor mdivi-1 Is a reversible mitochondrial complex I inhibitor that modulates reactive oxygen species. Dev Cell. 2017;40:583–94. e586.

    Article  CAS  Google Scholar 

  24. Choi YM, Kim HK, Shim W, Anwar MA, Kwon JW, Kwon HK, et al. Mechanism of cisplatin-induced cytotoxicity is correlated to impaired metabolism due to mitochondrial ROS generation. PLoS ONE. 2015;10:e0135083.

    Article  Google Scholar 

  25. Cristofani R, Montagnani Marelli M, Cicardi ME, Fontana F, Marzagalli M, Limonta P, et al. Dual role of autophagy on docetaxel-sensitivity in prostate cancer cells. Cell Death Dis. 2018;9:889.

    Article  Google Scholar 

  26. Lilly M, Sandholm J, Cooper JJ, Koskinen PJ, Kraft A. The PIM-1 serine kinase prolongs survival and inhibits apoptosis-related mitochondrial dysfunction in part through a bcl-2-dependent pathway. Oncogene. 1999;18:4022–31.

    Article  CAS  Google Scholar 

  27. Macdonald A, Campbell DG, Toth R, McLauchlan H, Hastie CJ, Arthur JS. Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. BMC Cell Biol. 2006;7:1.

    Article  Google Scholar 

  28. Westermann B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol. 2010;11:872–84.

    Article  CAS  Google Scholar 

  29. Nagdas S, Kashatus JA, Nascimento A, Hussain SS, Trainor RE, Pollock SR, et al. Drp1 promotes KRas-driven metabolic changes to drive pancreatic tumor growth. Cell Rep. 2019;28:1845–59. e1845.

    Article  CAS  Google Scholar 

  30. Wan J, Cui J, Wang L, Wu K, Hong X, Zou Y, et al. Excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer PANC-1 cell apoptosis via activating the mROS-HtrA2/Omi pathways. Cancer Cell Int. 2018;18:165.

    Article  CAS  Google Scholar 

  31. Senft D, Ronai ZA. Regulators of mitochondrial dynamics in cancer. Curr Opin Cell Biol. 2016;39:43–52.

    Article  CAS  Google Scholar 

  32. Kashatus DF, Lim KH, Brady DC, Pershing NL, Cox AD, Counter CM. RALA and RALBP1 regulate mitochondrial fission at mitosis. Nat Cell Biol. 2011;13:1108–15.

    Article  CAS  Google Scholar 

  33. Chang CR, Blackstone C. Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem. 2007;282:21583–7.

    Article  CAS  Google Scholar 

  34. Cribbs JT, Strack S. Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep. 2007;8:939–44.

    Article  CAS  Google Scholar 

  35. Din S, Mason M, Volkers M, Johnson B, Cottage CT, Wang Z, et al. Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation. Proc Natl Acad Sci USA. 2013;110:5969–74.

    Article  CAS  Google Scholar 

  36. Warfel NA, Kraft AS. PIM kinase (and Akt) biology and signaling in tumors. Pharm Ther. 2015;151:41–9.

    Article  CAS  Google Scholar 

  37. Tu ML, Wang HQ, Sun XD, Chen LJ, Peng XC, Yuan YH, et al. Pim-1 is up-regulated by shear stress and is involved in shear stress-induced proliferation of rat mesenchymal stem cells. Life Sci. 2011;88:233–8.

    Article  CAS  Google Scholar 

  38. Zemskova M, Sahakian E, Bashkirova S, Lilly M. The PIM1 kinase is a critical component of a survival pathway activated by docetaxel and promotes survival of docetaxel-treated prostate cancer cells. J Biol Chem. 2008;283:20635–44.

    Article  CAS  Google Scholar 

  39. Song JH, Singh N, Luevano LA, Padi SKR, Okumura K, Olive V, et al. Mechanisms behind resistance to PI3K inhibitor treatment induced by the PIM kinase. Mol Cancer Ther. 2018;17:2710–21.

    Article  CAS  Google Scholar 

  40. Mikkers H, Nawijn M, Allen J, Brouwers C, Verhoeven E, Jonkers J. et al. Mice deficient for all PIM kinases display reduced body size and impaired responses to hematopoietic growth factors. Mol Cell Biol. 2004;24:6104–15.

    Article  CAS  Google Scholar 

  41. Song JH, An N, Chatterjee S, Kistner-Griffin E, Mahajan S, Mehrotra S, et al. Deletion of Pim kinases elevates the cellular levels of reactive oxygen species and sensitizes to K-Ras-induced cell killing. Oncogene. 2014;34:3728–36.

  42. Warfel NA, Niederst M, Stevens MW, Brennan PM, Frame MC, Newton AC. Mislocalization of the E3 ligase, beta-transducin repeat-containing protein 1 (beta-TrCP1), in glioblastoma uncouples negative feedback between the pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1) and Akt. J Biol Chem. 2011;286:19777–88.

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank Donna Zhang (University of Arizona) for providing the H1299 Keap1−/− cell line and assistance with the acquisition and analysis of EPR results. We thank Adam R. Kohr for his assistance with graphic design. The research was supported by American Cancer Society grant RSG-16-159-01-CDD, American Lung Association grant LCD-504131, and Department of Defense PCRP Award (W81XWH-19-1-0455) to NAW. Cancer Center Support Grant P30CA023074 also provided support for this research.

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  1. Noel A. Warfel

    Present address: Levy Cancer Center, Rm 0977, 1515 N. Campbell Avenue, Tucson, AZ, 85724, USA

Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA

    Shailender S. Chauhan & Noel A. Warfel

  2. University of Arizona Cancer Center, Tucson, AZ, USA

    Rachel K. Toth & Noel A. Warfel

  3. Department of Cancer Biology, University of Arizona, Tucson, AZ, USA

    Corbin C. Jensen & Andrea L. Casillas

  4. Department of Microbiology, Immunology & Cancer Biology, University of Virginia, Charlottesville, VA, USA

    David F. Kashatus

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Contributions

Study concept and design: NAW and SSC. Acquisition of data: SSC, RKT, CCJ, ALC, and NAW. Analysis and presentation of data: NAW and SSC. Material support: DFA. Study supervision: NAW. Funding: NAW.

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Correspondence to Noel A. Warfel.

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Chauhan, S.S., Toth, R.K., Jensen, C.C. et al. PIM kinases alter mitochondrial dynamics and chemosensitivity in lung cancer. Oncogene 39, 2597–2611 (2020). https://doi.org/10.1038/s41388-020-1168-9

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