Multidrug resistance remains a major obstacle in gastric cancer therapy and is frequently associated with aggressive phenotypes. Although ABCG2 is a well-known drug efflux transporter, its functional contribution to paclitaxel (PTX) resistance and its relationship with ERK signaling in gastric cancer remain incompletely understood. In this study, PTX-resistant gastric cancer cell models were established through prolonged drug exposure. Resistant cells exhibited cross-resistance to cisplatin and 5-fluorouracil together with enhanced drug efflux activity, invasion capacity, spheroid formation, stemness-associated marker expression, and G0/G1 enrichment. ABCG2 expression was markedly increased in resistant cells. Stable knockdown of ABCG2 restored PTX sensitivity and significantly reduced drug efflux, invasion, spheroid formation, and stemness-associated phenotypes, while increasing apoptosis and altering cell cycle distribution. ABCG2 depletion was associated with reduced ERK phosphorylation and decreased expression of ERK downstream target genes. Pharmacological inhibition of ERK signaling similarly suppressed resistance-associated phenotypes and reduced ABCG2 expression. Whereas reactivation of ERK signaling by constitutively active MEK1 partially rescued the effects of ABCG2 depletion, restoring aggressive and multidrug-resistant phenotypes. Our findings indicate that ERK signaling functionally contributes to ABCG2-associated multidrug resistance and aggressive phenotypes in PTX-resistant gastric cancer cells.
Terzioğlu et al. (Tue,) studied this question.