Mitochondrial Uncouplers Inhibit Oncogenic E2F1 Activity and Prostate Cancer Growth

Authors

Ohuod Hawsawi
Weinan Xue
Tingting Du
Mengqi Guo
Xiaolin Yu
Mingyi Zhang
Paul S Hoffman
Roni Bollag
Jun Li
Jia Zhou
Hongbo Wang
Junran Zhang
Zheng Fu
Xiaoguang Chen
Chunhong Yan

Language

English

Publication Date

1-21-2025

Journal

Cell Reports Medicine

DOI

10.1016/j.xcrm.2024.101890

PMID

39793570

PMCID

PMC11866447

PubMedCentral® Posted Date

1-9-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Mitochondrial uncouplers dissipate proton gradients and deplete ATP production from oxidative phosphorylation (OXPHOS). While the growth of prostate cancer depends on OXPHOS-generated ATP, the oncogenic pathway mediated by the transcription factor E2F1 is crucial for the progression of this deadly disease. Here, we report that mitochondrial uncouplers, including tizoxanide (TIZ), the active metabolite of the Food and Drug Administration (FDA)-approved anthelmintic nitazoxanide (NTZ), inhibit E2F1-mediated expression of genes involved in cell cycle progression, DNA synthesis, and lipid synthesis. Consequently, NTZ/TIZ induces S-phase kinase-associated protein 2 (SKP2)-mediated G1 arrest while impeding DNA synthesis, lipogenesis, and the growth of prostate cancer cells. The anti-cancer activity of TIZ correlates with its OXPHOS-uncoupling activity. NTZ/TIZ appears to inhibit ATP production, thereby activating the AMP-activated kinase (AMPK)-p38 pathway, leading to cyclin D1 degradation, Rb dephosphorylation, and subsequent E2F1 inhibition. Our results thus connect OXPHOS uncoupling to the inhibition of an essential oncogenic pathway, supporting repositioning NTZ and other mitochondrial uncouplers for prostate cancer therapy.

Keywords

Male, E2F1 Transcription Factor, Humans, Prostatic Neoplasms, Mitochondria, Oxidative Phosphorylation, Cell Line, Tumor, Cell Proliferation, Uncoupling Agents, Thiazoles, AMP-Activated Protein Kinases, Nitro Compounds, Animals, Adenosine Triphosphate, Gene Expression Regulation, Neoplastic, Cyclin D1, mitochondrial uncoupler, nitazoxanide, tizoxanide, oxidative phosphorylation, E2F1, SKP2, AMPK, p38, cyclin D1, prostate cancer

Published Open-Access

yes

Recommended Citation

Hawsawi, Ohuod; Xue, Weinan; Du, Tingting; et al., "Mitochondrial Uncouplers Inhibit Oncogenic E2F1 Activity and Prostate Cancer Growth" (2025). Faculty, Staff and Student Publications. 6134.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6134