2. Academic Validation
  3. Colibactin Exerts Androgen-dependent and -independent Effects on Prostate Cancer

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

  • Eur Urol Oncol. 2025 Jun;8(3):716-730. doi: 10.1016/j.euo.2024.10.015.
Raag Agrawal 1,  Sarah Al-Hiyari 2,  Rupert Hugh-White 2,  Robert Hromas 3,  Yash Patel 2,  Elizabeth A Williamson 3,  Mohammed F E Mootor 2,  Alfredo Gonzalez 1,  Jianmin Fu 4,  Roni Haas 1,  Madison Jordan 1,  Brian L Wickes 5,  Ghouse Mohammed 6,  Mao Tian 1,  Molly J Doris 7,  Christian Jobin 8,  Kevin M Wernke 9,  Yu Pan 6,  Takafumi N Yamaguchi 2,  Seth B Herzon 9,  Paul C Boutros 10,  Michael A Liss 11
Affiliations

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.

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