DDX11 interacts with PARP1 to facilitate PARylation, thereby promoting gallbladder cancer progression and conferring gemcitabine resistance.

Abstract

Gemcitabine resistance poses a significant challenge in gallbladder cancer (GBC) treatment, necessitating exploration of its molecular mechanisms. This study focuses on DDX11, which is highly expressed in gemcitabine-resistant GBC cells, suggesting a potential role in DNA damage repair. We establish gemcitabine-resistant GBC cell lines and observe significantly higher DDX11 expression in these cells than in parental cells. Clinical tissue analysis through qRT-PCR, western blot analysis, and immunohistochemistry confirms elevated DDX11 levels in tumors compared with adjacent normal tissues. Functional assays demonstrate that DDX11 knockdown inhibits cell proliferation, colony formation, and tumor growth, while restoring gemcitabine sensitivity. Mechanistically, proteomic analysis and co-immunoprecipitation reveal that the interaction of DDX11 with PARP1 leads to increased poly(ADP-ribosyl)ation (PARylation), which promotes DNA repair and drug resistance. Notably, combining gemcitabine with the PARP inhibitor olaparib has synergistic anti-tumor effects on resistant cells. These findings indicate that DDX11 contributes to GBC progression and chemoresistance by regulating PARP1-mediated PARylation and that targeting this pathway with PARP inhibitors may overcome gemcitabine resistance. This study provides new insights into GBC drug resistance mechanisms and suggests that combining conventional chemotherapy with PARP inhibition is a potential therapeutic strategy for resistant patients. The DDX11-PARP1-PARylation axis represents a promising target for improving GBC treatment outcomes, particularly in gemcitabine-resistant patients.