Cell Metabolism
Volume 33, Issue 1, 5 January 2021, Pages 94-109.e8
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Article
Upregulation of Antioxidant Capacity and Nucleotide Precursor Availability Suffices for Oncogenic Transformation

https://doi.org/10.1016/j.cmet.2020.10.002Get rights and content
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Highlights

  • G6PD can effectively transform immortalized fibroblasts and epithelial cells

  • Forced G6PD expression bolsters antioxidant defense and nucleotide synthesis

  • G6PD activates NAD kinase to stimulate NADP+ biosynthesis and converts NADP+ to NADPH

  • Exogenous antioxidants and nucleosides suffice to transform murine and human cells

Summary

The emergence of cancer from diverse normal tissues has long been rationalized to represent a common set of fundamental processes. However, these processes are not fully defined. Here, we show that forced expression of glucose-6-phosphate dehydrogenase (G6PD) affords immortalized mouse and human cells anchorage-independent growth in vitro and tumorigenicity in animals. Mechanistically, G6PD augments the NADPH pool by stimulating NAD+ kinase-mediated NADP+ biosynthesis in addition to converting NADP+ to NADPH, bolstering antioxidant defense. G6PD also increases nucleotide precursor levels through the production of ribose and NADPH, promoting cell proliferation. Supplementation of antioxidants or nucleosides suffices to convert immortalized mouse and human cells into a tumorigenic state, and supplementation of both is required when their overlapping metabolic consequences are minimized. These results suggest that normal cells have a limited capacity for redox balance and nucleotide synthesis, and overcoming this limit might represent a key aspect of oncogenic transformation.

Keywords

oncogenic transformation
cancer metabolism
pentose phosphate pathway
G6PD
NAD kinase
NADPH
redox regulation
nucleotide synthesis
antioxidants
nucleosides

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Present address: Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA

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