2. Academic Validation
  3. Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer

Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer

  • Nat Cell Biol. 2020 Apr;22(4):476-486. doi: 10.1038/s41556-020-0496-x.
Xiaoguang Liu  # 1,  Kellen Olszewski  # 2,  Yilei Zhang  # 1,  Esther W Lim 3,  Jiejun Shi 4,  Xiaoshan Zhang 5,  Jie Zhang 1,  Hyemin Lee 1,  Pranavi Koppula 1 6,  Guang Lei 1,  Li Zhuang 1,  M James You 7,  Bingliang Fang 5,  Wei Li 4,  Christian M Metallo 3,  Masha V Poyurovsky 2,  Boyi Gan 8 9
Affiliations

Affiliations

  • 1 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Kadmon Corporation, New York, NY, USA.
  • 3 Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
  • 4 Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 5 Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6 The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 7 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • 9 The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. [email protected].
  • # Contributed equally.
PMID: 32231310 DOI: 10.1038/s41556-020-0496-x
Abstract

SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for Cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing Cancer cells with high levels of SLC7A11 (SLC7A11high) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11high Cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11high Cancer cells and suppress SLC7A11high tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11high cancers.

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