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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Crosstalks between inflammasome and autophagy in cancer
Journal of Hematology & Oncology Open Access 23 July 2020
High Expression of NEK2 and PIM1, but Not PIM3, Is Linked to an Aggressive Phenotype of Bronchopulmonary Neuroendocrine Neoplasms
Endocrine Pathology Open Access 05 June 2020
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res. 2016;5:288–300.
Lin JJ, Shaw AT. Resisting resistance: targeted therapies in lung cancer. Trends Cancer. 2016;2:350–64.
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.
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.
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.
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.
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.
Trotta AP, Chipuk JE. Mitochondrial dynamics as regulators of cancer biology. Cell Mol Life Sci. 2017;74:1999–2017.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Roberts ER, Thomas KJ. The role of mitochondria in the development and progression of lung cancer. Comput Struct Biotechnol J. 2013;6:e201303019.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Westermann B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol. 2010;11:872–84.
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.
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.
Senft D, Ronai ZA. Regulators of mitochondrial dynamics in cancer. Curr Opin Cell Biol. 2016;39:43–52.
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.
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.
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.
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.
Warfel NA, Kraft AS. PIM kinase (and Akt) biology and signaling in tumors. Pharm Ther. 2015;151:41–9.
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.
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.
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.
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.
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.
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.
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.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
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
This article is cited by
Mitochondrial dynamics regulators: implications for therapeutic intervention in cancer
Cell Biology and Toxicology (2022)
A systematic review on active sites and functions of PIM-1 protein
Human Cell (2022)
Direct phosphorylation and stabilization of HIF-1α by PIM1 kinase drives angiogenesis in solid tumors
Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment
Nature Reviews Cancer (2021)
Crosstalks between inflammasome and autophagy in cancer
Journal of Hematology & Oncology (2020)