Colibactin Exerts Androgen-dependent and -independent Effects on Prostate Cancer.
Abstract
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<sup>+</sup>) initiate cancers via induction of genomic instability. In PC, androgens promote oncogenic translocations. Our aim was to investigate the association of pks<sup>+</sup>E. coli with PC diagnosis and molecular architecture, and its relationship with androgens.
We quantified the association of pks<sup>+</sup>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.
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.
Our findings are consistent with synergistic induction of genome instability and kataegis by colibactin 742 and DHT in cell culture. Colibactin-producing pks<sup>+</sup> E. coli may plausibly contribute to PC etiology.
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.
EDRN PI Authors
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Medline Author List
- Agrawal R
- Al-Hiyari S
- Boutros PC
- Doris MJ
- Fu J
- Gonzalez A
- Haas R
- Herzon SB
- Hromas R
- Hugh-White R
- Jobin C
- Jordan M
- Liss MA
- Mohammed G
- Mootor MFE
- Pan Y
- Patel Y
- Tian M
- Wernke KM
- Wickes BL
- Williamson EA
- Yamaguchi TN