PMID- 27196781 OWN - NLM STAT- MEDLINE DCOM- 20170629 LR - 20200930 IS - 1538-8514 (Electronic) IS - 1535-7163 (Print) IS - 1535-7163 (Linking) VI - 15 IP - 7 DP - 2016 Jul TI - PIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species. PG - 1637-47 LID - 10.1158/1535-7163.MCT-15-1018 [doi] AB - 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. (c)2016 AACR. CI - (c)2016 American Association for Cancer Research. FAU - Warfel, Noel A AU - Warfel NA AD - 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. FAU - Sainz, Alva G AU - Sainz AG AD - UROC-PREP program, University of Arizona College of Undergraduate Studies, Tucson, Arizona. FAU - Song, Jin H AU - Song JH AD - Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona. University of Arizona Cancer Center, Tucson, Arizona. FAU - Kraft, Andrew S AU - Kraft AS AD - University of Arizona Cancer Center, Tucson, Arizona. Department of Medicine, University of Arizona, Tucson, Arizona. warfelna@email.arizona.edu Akraft@uacc.arizona.edu. LA - eng GR - P30 CA023074/CA/NCI NIH HHS/United States GR - R01 CA173200/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20160516 PL - United States TA - Mol Cancer Ther JT - Molecular cancer therapeutics JID - 101132535 RN - 0 (AZD1208) RN - 0 (Biphenyl Compounds) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Reactive Oxygen Species) RN - 0 (Thiazolidines) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-pim-1) RN - EC 2.7.11.1 (proto-oncogene proteins pim) SB - IM MH - Animals MH - Biphenyl Compounds/pharmacology MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Cell Survival/drug effects MH - Disease Models, Animal MH - Humans MH - Hypoxia/genetics/*metabolism MH - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism MH - Male MH - Mice MH - Models, Biological MH - NF-E2-Related Factor 2/*metabolism MH - Neoplasms/drug therapy/genetics/*metabolism/pathology MH - Prostatic Neoplasms/drug therapy/genetics/metabolism/pathology MH - Protein Binding MH - Protein Kinase Inhibitors/*pharmacology MH - Protein Transport MH - Proto-Oncogene Proteins c-pim-1/*antagonists & inhibitors MH - Reactive Oxygen Species/*metabolism MH - Signal Transduction/*drug effects MH - Thiazolidines/pharmacology MH - Xenograft Model Antitumor Assays PMC - PMC4936950 MID - NIHMS791768 EDAT- 2016/05/20 06:00 MHDA- 2017/07/01 06:00 PMCR- 2017/07/01 CRDT- 2016/05/20 06:00 PHST- 2016/01/18 00:00 [received] PHST- 2016/05/02 00:00 [accepted] PHST- 2016/05/20 06:00 [entrez] PHST- 2016/05/20 06:00 [pubmed] PHST- 2017/07/01 06:00 [medline] PHST- 2017/07/01 00:00 [pmc-release] AID - 1535-7163.MCT-15-1018 [pii] AID - 10.1158/1535-7163.MCT-15-1018 [doi] PST - ppublish SO - Mol Cancer Ther. 2016 Jul;15(7):1637-47. doi: 10.1158/1535-7163.MCT-15-1018. Epub 2016 May 16.