PIM kinases alter mitochondrial dynamics and chemosensitivity in lung cancer

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 intercellular 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 to chemotherapy and produced a synergistic anti-tumor 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.

High Expression of NEK2 and PIM1, but Not PIM3, Is Linked to an Aggressive Phenotype of Bronchopulmonary Neuroendocrine Neoplasms

“…Recent studies based on immunohistochemical staining found PIM1 to be highly expressed in NSCLC [41,42]. Moreover, increased PIM1 levels were associated with worse prognosis [41] and poorer response to chemotherapy in these tumors [42]. PIM1 was also showed to promote highly aggressive, neuroendocrine variant of prostate cancer by epigenetic changes in H19, suggesting it may be implicated in malignant neuroendocrine transformation [13].…”

“…Recent studies based on immunohistochemical staining found PIM1 to be highly expressed in NSCLC [41,42]. Moreover, increased PIM1 levels were associated with worse prognosis [41] and poorer response to chemotherapy in these tumors [42].…”

<p>Analysis of Key Genes Regulating the Warburg Effect in Patients with Gastrointestinal Cancers and Selective Inhibition of This Metabolic Pathway in Liver Cancer Cells</p>

“…It has been reported that inhibition of PIM kinases causes excessive mitochondrial fission or increased intracellular ROS production and apoptosis. 28 Also, PIM1 knockdown significantly accelerated apoptosis in myoblasts. 29 Therefore, PIM1 may have different roles in different cancer types.…”

“The Loss of Golden Touch”: Mitochondria-Organelle Interactions, Metabolism, and Cancer

“…Consistent results were obtained in the KRas mutant non-small-cell lung cancer (NSCLC), where DRP1 orchestrated a metabolic rewiring to promote lactate utilization and ROS production suppression [ 62 ]. In the same type of tumor, DRP1 was involved in metabolic rearrangements that favored resistance to chemotherapy [ 63 ]. The authors identified a molecular axis represented by Proto-Oncogene Serine/Threonine-Protein Kinase (PIM1), DRP1, and mitochondrial fission; PIM1 inhibition favored DRP1 activity and mitochondrial fragmentation, increasing mitochondrial ROS production and resistance to pharmacological therapy [ 63 ].…”

“…In the same type of tumor, DRP1 was involved in metabolic rearrangements that favored resistance to chemotherapy [ 63 ]. The authors identified a molecular axis represented by Proto-Oncogene Serine/Threonine-Protein Kinase (PIM1), DRP1, and mitochondrial fission; PIM1 inhibition favored DRP1 activity and mitochondrial fragmentation, increasing mitochondrial ROS production and resistance to pharmacological therapy [ 63 ]. Further studies suggested an antitumoral property of DRP1 in other types of lung cancer.…”