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

Area of Science:

• Oncology
• Microbiology
• Genetics

Background:

• Prostate cancer (PC) etiology is multifactorial and not fully understood.
• Colibactin-producing Escherichia coli (pks+ E. coli) are implicated in cancer initiation via genomic instability.
• Androgens are known to promote oncogenic translocations in PC.

Purpose of the Study:

• To investigate the association between pks+ E. coli and PC diagnosis.
• To explore the relationship between pks+ E. coli, PC molecular architecture, and androgens.
• To evaluate the in vitro effects of colibactin and dihydrotestosterone (DHT) on PC cells.

Main Methods:

• Quantified association of pks+ E. coli with PC diagnosis in a 235-person cohort.
• Utilized colibactin 742 and DNA/RNA sequencing for in vitro experiments.
• Assessed effects of colibactin 742, DHT, and their combination on cell lines.

Main Results:

• Colibactin exposure showed a positive association with PC diagnosis (p=0.04).
• In vitro, colibactin significantly increased replication fork stalling and fusions (p<0.01).
• Combined colibactin and DHT exposure induced more somatic mutations and kataegis than either agent alone.

Conclusions:

• Findings suggest synergistic induction of genome instability and kataegis by colibactin and DHT in cell culture.
• Colibactin-producing pks+ E. coli are a plausible contributor to prostate cancer etiology.