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Mitochondrial uncouplers inhibit oncogenic E2F1 activity and prostate cancer growth

Ohuod Hawsawi1, Weinan Xue1, Tingting Du2

  • 1Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.

Cell Reports. Medicine
|January 10, 2025
PubMed

Insights

Mitochondrial uncouplers like nitazoxanide (NTZ) inhibit prostate cancer growth by blocking the E2F1 pathway. This FDA-approved drug disrupts energy production, offering a new therapeutic strategy for prostate cancer.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Prostate cancer growth relies on ATP from oxidative phosphorylation (OXPHOS).
  • The E2F1 pathway is critical for prostate cancer progression.
  • Mitochondrial uncouplers disrupt cellular energy production.

Purpose of the Study:

  • To investigate the effect of mitochondrial uncouplers on E2F1-mediated pathways in prostate cancer.
  • To determine if nitazoxanide (NTZ) and its metabolite tizoxanide (TIZ) can inhibit prostate cancer cell growth.
  • To explore the underlying molecular mechanisms of NTZ/TIZ anti-cancer activity.

Main Methods:

  • Treatment of prostate cancer cells with NTZ/TIZ.
  • Analysis of gene expression related to cell cycle, DNA synthesis, and lipid synthesis.
  • Assessment of cell cycle arrest, DNA synthesis, and lipogenesis.
  • Investigation of the AMP-activated kinase (AMPK)-p38 signaling pathway.

Main Results:

  • NTZ/TIZ inhibited E2F1-mediated gene expression crucial for cell cycle and biosynthesis.
  • NTZ/TIZ induced G1 cell cycle arrest and impeded DNA synthesis and lipogenesis.
  • The anti-cancer effects of TIZ correlated with its OXPHOS-uncoupling activity.
  • NTZ/TIZ activated the AMPK-p38 pathway, leading to E2F1 inhibition.

Conclusions:

  • Mitochondrial uncoupling inhibits a key oncogenic pathway in prostate cancer.
  • NTZ/TIZ demonstrates anti-cancer activity by disrupting OXPHOS and inhibiting E2F1.
  • Repositioning NTZ and other mitochondrial uncouplers for prostate cancer therapy is supported.
Keywords:
AMPKE2F1SKP2cyclin D1mitochondrial uncouplernitazoxanideoxidative phosphorylationp38prostate cancertizoxanide

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