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Oxidative pentose phosphate pathway inhibition is a key determinant of antimalarial induced cancer cell death

Oncogene volume 35, pages 2913–2922 (2016)Cite this article

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Abstract

Despite immense interest in using antimalarials as autophagy inhibitors to treat cancer, it remains unclear whether these agents act predominantly via autophagy inhibition or whether other pathways direct their anti-cancer properties. By comparing the treatment effects of the antimalarials chloroquine (CQ) and quinacrine (Q) on KRAS mutant lung cancer cells, we demonstrate that inhibition of the oxidative arm of the pentose phosphate pathway (oxPPP) is required for antimalarial induced apoptosis. Despite inhibiting autophagy, neither CQ treatment nor RNAi against autophagy regulators (ATGs) promote cell death. In contrast, Q triggers high levels of apoptosis, both in vitro and in vivo, and this phenotype requires both autophagy inhibition and p53-dependent inhibition of the oxPPP. Simultaneous genetic targeting of the oxPPP and autophagy is sufficient to trigger apoptosis in lung cancer cells, including cells lacking p53. Thus, in addition to reduced autophagy, oxPPP inhibition serves as an important determinant of antimalarial cytotoxicity in cancer cells.

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Acknowledgements

Grant support to JD includes the NIH (R01CA126792 and R01CA188404), California Tobacco Related Diseases Research Program (18XT-0106) and Samuel Waxman Cancer Research Foundation.

Author contributions

JD and BR conceived the study. ES, SR, TM and JD designed the experiments. ES, SR and TM performed the experiments. ES, SR, TM and JD analyzed the data. JD supervised the study and wrote the paper with input from the other authors.

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Authors and Affiliations

  1. Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA

    E Salas, S Roy, T Marsh & J Debnath

  2. Departments of Anatomic Pathology and Molecular Genetics, Cleveland Clinic, Cleveland, OH, USA

    B Rubin

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  1. E Salas
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  2. S Roy
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  3. T Marsh
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  5. J Debnath
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Correspondence to J Debnath.

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Salas, E., Roy, S., Marsh, T. et al. Oxidative pentose phosphate pathway inhibition is a key determinant of antimalarial induced cancer cell death. Oncogene 35, 2913–2922 (2016). https://doi.org/10.1038/onc.2015.348

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  • DOI: https://doi.org/10.1038/onc.2015.348

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