Colibactin Exerts Androgen-dependent and -independent Effects on Prostate Cancer

Raag Agrawal; Sarah Al-Hiyari; Rupert Hugh-White; Robert Hromas; Yash Patel; Elizabeth A Williamson; Mohammed F E Mootor; Alfredo Gonzalez; Jianmin Fu; Roni Haas; Madison Jordan; Brian L Wickes; Ghouse Mohammed; Mao Tian; Molly J Doris; Christian Jobin; Kevin M Wernke; Yu Pan; Takafumi N Yamaguchi; Seth B Herzon; Paul C Boutros; Michael A Liss

doi:10.1016/j.euo.2024.10.015

Colibactin Exerts Androgen-dependent and -independent Effects on Prostate Cancer

Eur Urol Oncol. 2024 Nov 14:S2588-9311(24)00245-1. doi: 10.1016/j.euo.2024.10.015. Online ahead of print.

Authors

Raag Agrawal¹, Sarah Al-Hiyari², Rupert Hugh-White², Robert Hromas³, Yash Patel², Elizabeth A Williamson³, Mohammed F E Mootor², Alfredo Gonzalez¹, Jianmin Fu⁴, Roni Haas¹, Madison Jordan¹, Brian L Wickes⁵, Ghouse Mohammed⁶, Mao Tian¹, Molly J Doris⁷, Christian Jobin⁸, Kevin M Wernke⁹, Yu Pan⁶, Takafumi N Yamaguchi², Seth B Herzon⁹, Paul C Boutros¹⁰, Michael A Liss¹¹

Affiliations

¹ Department of Human Genetics, University of California-Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California-Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA.
² Department of Human Genetics, University of California-Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California-Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California-Los Angeles, Los Angeles, CA, USA.
³ Division of Hematology and Medical Oncology, Department of Medicine and the Mays Cancer Center, University of Texas Health-San Antonio, San Antonio, TX, USA.
⁴ Department of Microbiology and Immunology, University of Texas Health-San Antonio, San Antonio, TX, USA.
⁵ Department of Microbiology, Immunology, and Molecular Genetics, University of Texas, San Antonia, TC, USA.
⁶ Office of Health Informatics and Analytics, University of California-Los Angeles, Los Angeles, CA, USA.
⁷ Department of Urology, University of Texas Health-San Antonio, San Antonio, TX, USA.
⁸ Departments of Medicine, Infectious Diseases and Immunology, and Anatomy and Cell Physiology, University of Florida, Gainesville, FL, USA.
⁹ Department of Chemistry, Yale University, New Haven, CT, USA; Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA.
¹⁰ Department of Human Genetics, University of California-Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California-Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California-Los Angeles, Los Angeles, CA, USA; Department of Medical Biophysics, University of Toronto, Toronto, Canada.
¹¹ Department of Urology, University of Texas Health-San Antonio, San Antonio, TX, USA. Electronic address: [email protected].

PMID: 39547899
DOI: 10.1016/j.euo.2024.10.015

Abstract

Background and objective: The etiology of prostate cancer (PC) is multifactorial and poorly understood. It has been suggested that colibactin-producing Escherichia coli positive for the pathogenicity island pks (pks⁺) initiate cancers via induction of genomic instability. In PC, androgens promote oncogenic translocations. Our aim was to investigate the association of pks⁺E. coli with PC diagnosis and molecular architecture, and its relationship with androgens.

Methods: We quantified the association of pks⁺E. coli with PC diagnosis in a volunteer-sampled 235-person cohort from two institutional practices (UT San Antonio). We then used colibactin 742 and DNA/RNA sequencing to evaluate the effects of colibactin 742, dihydrotestosterone (DHT), and their combination in vitro.

Key findings and limitations: Colibactin exposure was positively associated with PC diagnosis (p = 0.04) in our clinical cohort, and significantly increased replication fork stalling and fusions in vitro (p < 0.01). Combined in vitro exposure to colibactin 742 and DHT induced more somatic mutations of all types than exposure to either alone. The combination also elicited kataegis, with a higher density of somatic point mutations. Laboratory analyses were conducted using a single cell line, which limited our ability to fully recapitulate the complexity of PC etiology.

Conclusions and clinical implications: Our findings are consistent with synergistic induction of genome instability and kataegis by colibactin 742 and DHT in cell culture. Colibactin-producing pks⁺ E. coli may plausibly contribute to PC etiology.

Patient summary: We investigated whether a bacterial toxin that is linked to colon cancer can also cause prostate cancer. Our results support this idea by showing a link between the toxin and prostate cancer diagnosis in a large patient population. We also found that this toxin causes genetic dysfunction in prostate cancer cells when combined with testosterone.

Grants and funding

R01 CA215553/CA/NCI NIH HHS/United States