Mitochondrial uncouplers inhibit oncogenic E2F1 activity and prostate cancer growth
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.
Authors
- Roni J. Bollag (ORCID: https://orcid.org/0000-0003-4963-6619)
- Paul S. Hoffman (ORCID: https://orcid.org/0000-0001-5131-1077)
- Zheng Qing Fu (ORCID: https://orcid.org/0000-0003-1519-6192)
- Chunhong Yan (ORCID: https://orcid.org/0000-0002-3974-7991)
- Ohuod Hawsawi
- J. Li (ORCID: https://orcid.org/0000-0001-8560-9306)
- Junran Zhang (ORCID: https://orcid.org/0000-0001-5413-3675)
- Xiaolin Yu (ORCID: https://orcid.org/0000-0003-3256-0638)
- Tingting Du (ORCID: https://orcid.org/0000-0002-1350-6778)
- Weinan Xue
- Jia Zhou (ORCID: https://orcid.org/0000-0001-5262-4876)
- Xiao‐Guang Chen (ORCID: https://orcid.org/0000-0002-7927-691X)
- Mingyi Zhang (ORCID: https://orcid.org/0000-0002-4970-2973)
- Mengqi Guo
- Hongbo Wang (ORCID: https://orcid.org/0000-0003-1591-297X)
Institutions
- Yantai University (CN)
- Virginia Commonwealth University (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Augusta University (US)
- Augusta University Health (US)
- University of Virginia (US)
- The Ohio State University (US)
- The University of Texas Medical Branch at Galveston (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101890
- Citations
- 7
- Primary Topic
- Cancer-related Molecular Pathways
- Type
- article
- Field-Weighted Citation Impact
- 7.32
Funders
- U.S. Department of Defense
- Foundation for the National Institutes of Health
- National Institutes of Health