ARTN drives ABCB1-mediated chemoresistance in gastric cancer cells by promoting ELK4 phosphorylation.

BACKGROUND

Chemoresistance is the primary hindrance to effective gastric cancer (GC) treatment. Artemin (ARTN) exerts oncogenic roles in various malignancies (including GC), yet its involvement in GC chemoresistance remains unelucidated. This work sought to clarify the function of ARTN and the mechanism in GC chemoresistance.

METHODS

ARTN expression was detected via qPCR and western blotting. The functions of ARTN in GC chemoresistance were evaluated in vitro by CCK-8, apoptosis, and colony formation assays, which were also determined in vivo using a xenograft mouse model. Immunohistochemistry was adopted to measure Ki67 (a marker of proliferation) and cleaved caspase 3 (a marker of apoptosis) in tumor tissues. ELK4 phosphorylation was assessed through immunoprecipitation and western blotting. ChIP-qPCR was employed to determine the binding of ELK4 and ABCB1.

RESULTS

ARTN was aberrantly upregulated in GC cells, particularly in chemo-resistant GC cells; its knockdown efficaciously sensitized chemo-resistant GC cells to 5-fluorouracil (5-FU), reduced proliferation, and enhanced apoptosis. In vivo, ARTN deficiency restrained tumor growth in chemo-resistant xenograft mice under 5-FU treatment, with downregulated Ki67 and upregulated cleaved caspase 3 in tumor tissues. Molecular mechanism experiments revealed that ARTN facilitated ELK4 phosphorylation and increase ABCB1 expression in GC cells by activating KRAS/ERK signaling. Crucially, ARTN overexpression impaired GC cell sensitivity to 5-FU in vitro, which was abrogated by ELK4 or ABCB1 knockdown.

CONCLUSION

ARTN promotes GC chemoresistance by upregulating ABCB1 expression via modulating ELK4 phosphorylation, offering a likely therapeutic approach to reverse GC chemoresistance.