PIM Kinase inhibitors kill hypoxic tumor cells by reducing Nrf2 signaling and increasing reactive oxygen species

Noel A. Warfel, Alva G. Sainz, Jin H. Song, Andrew Kraft

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1637-1647
Number of pages11
JournalMolecular Cancer Therapeutics
Volume15
Issue number7
DOIs
StatePublished - Jul 1 2016

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Reactive Oxygen Species
Phosphotransferases
Poisons
Neoplasms
Tumor Microenvironment
Moloney murine leukemia virus
Cell Hypoxia
Disease Resistance
Cystine
Therapeutics
Heterografts
Superoxide Dismutase
Oxidative Stress
Cell Death
Antioxidants
Neoplasm Metastasis
Gene Expression
Recurrence
Hypoxia
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

PIM Kinase inhibitors kill hypoxic tumor cells by reducing Nrf2 signaling and increasing reactive oxygen species. / Warfel, Noel A.; Sainz, Alva G.; Song, Jin H.; Kraft, Andrew.

In: Molecular Cancer Therapeutics, Vol. 15, No. 7, 01.07.2016, p. 1637-1647.

Research output: Contribution to journalArticle

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