PIM kinases alter mitochondrial dynamics and chemosensitivity in lung cancer

Oncogene. 2020 Mar;39(12):2597-2611. doi: 10.1038/s41388-020-1168-9. Epub 2020 Jan 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Datasets as Topic
  • Docetaxel / therapeutic use*
  • Drug Resistance, Neoplasm
  • Dynamins / metabolism
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / metabolism*
  • Mice
  • Mice, SCID
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondrial Dynamics*
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-pim-1 / metabolism*
  • Reactive Oxygen Species / metabolism
  • Treatment Outcome
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Reactive Oxygen Species
  • Docetaxel
  • Proto-Oncogene Proteins c-pim-1
  • proto-oncogene proteins pim
  • Dnm1l protein, mouse
  • Dynamins