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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Inhibiting system xC- and glutathione biosynthesis - a potential Achilles' heel in mutant-p53 cancers

Nicholas J Clemons1,2, David S Liu1,2,3,4, Cuong P Duong3

  • 1Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Molecular & Cellular Oncology
|October 24, 2017
PubMed

Insights

Mutant p53 protein in cancer impairs NRF2 function and reduces glutathione, making these tumors vulnerable to therapies targeting the SLC7A11/glutathione pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Targeting mutant tumor protein p53 (TP53) in cancers is a significant unmet medical need.
  • Mutant p53 is frequently observed in various human cancers, driving tumor progression and therapy resistance.

Purpose of the Study:

  • To investigate the functional consequences of mutant p53 on cellular metabolism and identify potential therapeutic vulnerabilities.
  • To elucidate the role of mutant p53 in regulating the NRF2 pathway and glutathione synthesis.

Main Methods:

  • Utilized molecular biology techniques to assess the impact of mutant p53 on NRF2 activity.
  • Quantified solute carrier family 7 member 11 (SLC7A11) expression and cellular glutamate/cystine exchange.
  • Analyzed glutathione biosynthesis and redox balance in mutant p53-expressing cells.

Main Results:

  • Mutant p53 was found to impair nuclear factor (erythroid-derived 2)-like 2 (NFE2L2, NRF2) function.
  • Mutant p53 suppressed SLC7A11 expression, leading to diminished cellular glutamate/cystine exchange.
  • This resulted in decreased glutathione biosynthesis and a subsequent redox imbalance in mutant p53 tumors.

Conclusions:

  • Mutant p53-expressing tumors exhibit an inherent susceptibility to disruptions in the SLC7A11/glutathione axis.
  • Targeting the SLC7A11/glutathione pathway represents a promising therapeutic strategy for mutant p53 cancers.
Keywords:
APR-246NFE2L2NRF2PRIMA-1metSLC7A11glutathione (GSH)p53reactive oxygen species (ROS)system xC−xCT

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