BACKGROUND-AIM
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. Epidemiological studies demonstrate that men have a higher CRC incidence rate and face worse survival outcomes compared to women. This gender disparity in CRC incidence and outcomes pushed us to explore the mechanisms by which the androgen receptor (AR) may influence its pathology. Interestingly, the roles of the AR in cancer extend beyond traditional hormone-dependent cancers; in fact, in recent years, researchers have identified that AR signaling is also implicated in the progression of other cancers that do not typically respond to hormonal regulation. Understanding how AR mediates CRC's aggressiveness could provide valuable insights that may help to find more effective treatment strategies.
METHODS
In this study, we used CRC-derived Caco2, LoVo, and HCT-116 cells, expressing the AR to different extents. A BrdU incorporation assay and the measurement of spheroid growth were used to monitor cell proliferation. Biochemical approaches such as co-immunoprecipitation, immunoblotting, and immunofluorescence show that androgen treatment induces an interaction between the AR and Filamin A and the activation of different effectors without altering AR cell localization.
RESULTS
Our findings demonstrate that, in CRC cells, androgen treatment triggers an interaction between the AR and Filamin A. This complex activates Rac, p70, PKCs, and other proteins, thereby controlling different CRC-derived cells' proliferation. The antiandrogen Bicalutamide and a small peptide, Rh2025u, designed to mimic the AR sequences responsible for the AR/Filamin A interaction, reverse the androgen-induced effects in all cell lines.
CONCLUSIONS
This study underscores the significance of the AR in CRC and suggests that variations in androgen levels may influence both the onset and progression of this disease. By elucidating the role of the AR in CRC, this research opens avenues for innovative screening strategies and the development of targeted therapies.
