Transcriptional activation of GSTP1 by ANXA3 is associated with cisplatin sensitivity in colorectal cancer cells.

Although platinum-based chemotherapeutic agents demonstrate efficacy against colorectal cancer (CRC), the development of resistance to these agents remains a notable clinical challenge, with the underlying mechanisms still incompletely understood. In the present study, public tumor databases revealed that annexin A3 (ANXA3) was significantly upregulated in CRC primary tumors. This upregulation was then validated at the protein level using a tissue microarray, which confirmed elevated ANXA3 expression in CRC tumor tissues. The Kaplan-Meier curve analysis further demonstrated that patients with CRC with high ANXA3 expression exhibited shorter overall survival compared with those with low expression. Notably, CRC cell lines with high ANXA3 expression showed reduced sensitivity to cisplatin. Moreover, overexpression of ANXA3 significantly diminished cisplatin sensitivity in CRC cells, whereas silencing ANXA3 enhanced this sensitivity. These results collectively indicated that ANXA3 modulated cisplatin sensitivity in CRC cells. Subsequent investigations revealed that ANXA3 upregulated glutathione S-transferase P1 (GSTP1) expression in CRC cells in an NF-κB-dependent manner, a pathway mechanistically implicated in clinically observed chemotherapy resistance. In addition, ANXA3-overexpressing exosomes were found to upregulate GSTP1 transcriptional expression and decrease cisplatin sensitivity in CRC cells. Finally, in silico molecular docking predicted K201 as a potential ANXA3-interacting compound. Further investigations revealed that combination treatment with K201 and cisplatin significantly enhanced tumor inhibition compared with cisplatin monotherapy in CRC cell models. In conclusion, using in vitro experiments, the current study demonstrated that targeting ANXA3 may represent a promising strategy for overcoming cisplatin resistance in CRC. However, further in vivo validations, particularly regarding the therapeutic relevance of the ANXA3-GSTP1 axis and K201, are warranted to substantiate its clinical potential.