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TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism

Jie Cheng1, Yan Huang1, Xiaohui Zhang2

  • 1The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, 100871, China.

Nature Communications
|April 22, 2020
PubMed

Insights

This study reveals a two-way street between PI3K/AKT signaling and the pentose phosphate pathway (PPP) in cancer. Blocking this crosstalk may offer new cancer therapies, especially for PTEN-deficient tumors.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • The PI3K/AKT pathway is crucial for cancer metabolism.
  • The role of metabolic feedback in regulating the PI3K/AKT pathway remains largely unknown.

Purpose of the Study:

  • To investigate the reciprocal crosstalk between PI3K/AKT signaling and the pentose phosphate pathway (PPP).
  • To explore the therapeutic potential of targeting this crosstalk in cancer treatment.

Main Methods:

  • Investigated the stabilization of Glucose-6-phosphate dehydrogenase (G6PD) by PI3K/AKT signaling via TIRM21 inhibition.
  • Examined the reinforcement of AKT activation by PPP metabolites through PHLDA3 expression blockade.
  • Utilized knockout models of TRIM21 and PHLDA3.
  • Assessed sensitivity to anti-PPP treatments in PTEN-null cancer cells and murine models.

Main Results:

  • PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of the PPP, by inhibiting TIRM21, thereby promoting the PPP.
  • PPP metabolites enhance AKT activation and cancer metabolic reprogramming by suppressing PHLDA3 expression.
  • TRIM21 or PHLDA3 knockout accelerates crosstalk and cell proliferation.
  • PTEN-null cancers exhibit sensitivity to anti-PPP treatments, highlighting PPP's role in maintaining AKT activation.

Conclusions:

  • A reciprocal crosstalk exists between PI3K/AKT signaling and the PPP, crucial for cancer metabolism.
  • Targeting this crosstalk, particularly in PTEN-loss or PI3K/AKT-activated cancers, may offer therapeutic benefits.

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