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The positive feedback loop between Nrf2 and phosphogluconate dehydrogenase stimulates proliferation and clonogenicity

Athena Jessica Ong1, Soma Saeidi1,2, Ngo Hoang Kieu Chi1

  • 1Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.

Free Radical Research
|April 28, 2020
PubMed

Insights

Nuclear factor-erythroid-2-related factor 2 (Nrf2) drives cancer growth by increasing phosphogluconate dehydrogenase (PGD). This study reveals a positive feedback loop between Nrf2 and PGD in hepatoma cells, crucial for their proliferation and survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Nuclear factor-erythroid-2-related factor 2 (Nrf2) is implicated in cancer progression via metabolic reprogramming.
  • The precise molecular mechanisms of Nrf2's oncogenic functions remain unclear.
  • Pentose phosphate pathway (PPP) enzymes are increasingly recognized for their role in cancer progression.

Purpose of the Study:

  • To investigate the role of phosphogluconate dehydrogenase (PGD), a PPP enzyme, in the proliferation and migration of human hepatoma HepG2 cells.
  • To elucidate the regulatory relationship between Nrf2 and PGD in hepatoma cells.

Main Methods:

  • Genetic manipulation of Nrf2 and PGD expression in HepG2 cells (gene ablation, overexpression, knockdown).
  • Analysis of gene and protein expression levels.
  • Assessment of cell proliferation, survival, migration, and clonogenicity.
  • Reporter assays to confirm transcriptional regulation via antioxidant response element (ARE).

Main Results:

  • Nrf2 genetic ablation reduced PGD expression at transcriptional and translational levels.
  • Nrf2 directly binds to the ARE in the PGD promoter, regulating its transcription.
  • Nrf2 overexpression enhanced HepG2 cell proliferation, survival, and migration, effects reversed by PGD silencing.
  • PGD knockdown inhibited HepG2 cell proliferation and clonogenicity and downregulated Nrf2 expression.
  • A positive feedback loop between Nrf2 and PGD was identified, promoting hepatoma cell growth.
  • Ribulose-5-phosphate treatment upregulated Nrf2 in a concentration-dependent manner.

Conclusions:

  • Nrf2 promotes hepatoma cell growth and progression, partly by inducing PGD transcription.
  • A positive feedback loop exists between Nrf2 and PGD, essential for hepatoma cell proliferation and survival.
  • Targeting the Nrf2-PGD axis may offer therapeutic strategies for hepatoma treatment.
Keywords:
Nrf2human hepatoma HepG2 cellspentose phosphate pathwayphosphogluconate dehydrogenaseribulose-5-phosphate

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