title: PIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species.
abstract: Intratumoral hypoxia is a significant obstacle to the successful treatment of solid tumors, and it is highly correlated with metastasis, therapeutic resistance, and disease recurrence in cancer patients. As a result, there is an urgent need to develop effective therapies that target hypoxic cells within the tumor microenvironment. The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases represent a prosurvival pathway that is upregulated in response to hypoxia, in a HIF-1-independent manner. We demonstrate that pharmacologic or genetic inhibition of PIM kinases is significantly more toxic toward cancer cells in hypoxia as compared with normoxia. Xenograft studies confirm that PIM kinase inhibitors impede tumor growth and selectively kill hypoxic tumor cells in vivo Experiments show that PIM kinases enhance the ability of tumor cells to adapt to hypoxia-induced oxidative stress by increasing the nuclear localization and activity of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), which functions to increase the expression of antioxidant genes. Small molecule PIM kinase inhibitors prevent Nrf2 from accumulating in the nucleus, reducing the transcription of cytoprotective genes and leading to the build-up of intracellular reactive oxygen species (ROS) to toxic levels in hypoxic tumor cells. This toxic effect of PIM inhibitors can be successfully blocked by ROS scavengers, including N-acetyl cystine and superoxide dismutase. Thus, inhibition of PIM kinases has the potential to oppose hypoxia-mediated therapeutic resistance and induce cell death in the hypoxic tumor microenvironment. Mol Cancer Ther; 15(7); 1637-47. ©2016 AACR.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona. University of Arizona Cancer Center, Tucson, Arizona. warfelna@email.arizona.edu Akraft@uacc.arizona.edu.
authors.forename: Noel A
authors.initials: NA
authors.lastname: Warfel
authors.affiliation: UROC-PREP program, University of Arizona College of Undergraduate Studies, Tucson, Arizona.
authors.forename: Alva G
authors.initials: AG
authors.lastname: Sainz
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona. University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Jin H
authors.initials: JH
authors.lastname: Song
authors.affiliation: University of Arizona Cancer Center, Tucson, Arizona. Department of Medicine, University of Arizona, Tucson, Arizona. warfelna@email.arizona.edu Akraft@uacc.arizona.edu.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Kraft
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D021381:Protein Transport; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D053778:Thiazolidines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C587575:AZD1208; D001713:Biphenyl Compounds; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051267:NF-E2-Related Factor 2; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D053778:Thiazolidines; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim