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Transketolase regulates sensitivity to APR-246 in p53-null cells independently of oxidative stress modulation

Julia V Milne1,2, Bonnie Z Zhang1,2, Kenji M Fujihara1,2

  • 1Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC, 3000, Australia.

Scientific Reports
|February 25, 2021
PubMed

Insights

Tumor suppressor p53 mutations are common. Inhibiting SLC7A11 enhances sensitivity to APR-246 therapy. This study explores the role of TKT in this synergy, finding TKT expression determines drug sensitivity in p53-null cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Mutations in the tumor suppressor p53 are prevalent and drive cancer progression.
  • Inhibition of SLC7A11 enhances sensitivity to mutant-p53 targeted therapy (APR-246).
  • The pentose phosphate pathway (PPP) and its enzyme TKT are potential modulators of drug sensitivity.

Purpose of the Study:

  • To investigate the relationship between mutant-p53, TKT expression, and sensitivity to APR-246.
  • To determine if TKT modulates the synergistic effect of SLC7A11 inhibition with APR-246 therapy.

Main Methods:

  • Investigated TKT expression in relation to mutant-p53 and NRF2.
  • Utilized TKT knockdown and overexpression in p53-null and mutant-p53 expressing cells.
  • Assessed cellular sensitivity to APR-246 and oxidative stress levels.

Main Results:

  • Mutant-p53 did not alter TKT expression; NRF2 did not directly modulate TKT.
  • In p53-null cells, TKT knockdown increased APR-246 sensitivity, while TKT overexpression conferred resistance.
  • These effects were not observed in cells overexpressing mutant-p53, despite similar oxidative stress mediation.

Conclusions:

  • TKT expression is a key determinant of sensitivity to APR-246 in p53-null cancer cells.
  • The mechanism of TKT's influence on APR-246 sensitivity is complex and p53-dependent.
  • Targeting TKT may offer a strategy to enhance APR-246 efficacy in specific cancer contexts.

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