Mitochondrial uncouplers inhibit oncogenic E2F1 activity and prostate cancer growth

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

doi:10.1016/j.xcrm.2024.101890

Mitochondrial uncouplers inhibit oncogenic E2F1 activity and prostate cancer growth

Cell Rep Med. 2024 Dec 30:101890. doi: 10.1016/j.xcrm.2024.101890. Online ahead of print.

Authors

Ohuod Hawsawi¹, Weinan Xue¹, Tingting Du², Mengqi Guo³, Xiaolin Yu¹, Mingyi Zhang², Paul S Hoffman⁴, Roni Bollag¹, Jun Li⁵, Jia Zhou⁵, Hongbo Wang⁶, Junran Zhang⁷, Zheng Fu⁸, Xiaoguang Chen⁹, Chunhong Yan¹⁰

Affiliations

¹ Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
² Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Institute of Materia Medica, Peking Union Medical College, Beijing 100050, China.
³ Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; College of Pharmacy, Yantai University, Yantai, Shandong Province 264005, China.
⁴ Division of Infectious Diseases & International Health, University of Virginia, Charlottesville, VA 22903, USA.
⁵ Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
⁶ College of Pharmacy, Yantai University, Yantai, Shandong Province 264005, China.
⁷ Department of Radiation Oncology, Ohio State University, Columbus, OH 43210, USA.
⁸ Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
⁹ Institute of Materia Medica, Peking Union Medical College, Beijing 100050, China.
¹⁰ Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. Electronic address: cyan@augusta.edu.

PMID: 39793570
DOI: 10.1016/j.xcrm.2024.101890

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: AMPK; E2F1; SKP2; cyclin D1; mitochondrial uncoupler; nitazoxanide; oxidative phosphorylation; p38; prostate cancer; tizoxanide.