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.

1. Introduction

Gallbladder carcinoma (GBC) is a highly malignant tumor of the biliary system with a poor prognosis [1,2]. Its incidence among gastrointestinal tumors is relatively low (< 2 per 100,000), with a higher prevalence in females than in males [3]. Globally, there are approximately 116,000 new cases and 85,000 deaths annually, predominantly in the Far East and South American regions [1]. Current gemcitabine-platinum combination chemotherapies have shown limited efficacy (< 30% response rate) [4,5], and the 5-year survival rate remains at approximately 18% [6], highlighting significant clinical challenges.

Moreover, chemoresistance represents a major therapeutic obstacle [7], classified as either acquired (recurrence after initial response) or intrinsic (primary nonresponse) [8]. Underlying mechanisms include drug efflux upregulation [9], metabolic reprogramming, target mutations, apoptosis evasion [10], epigenetic alterations [11], and microenvironment remodeling [12,13]. Biomarker-guided personalized therapies may improve outcomes [8,14].

While genomic studies have characterized GBC molecular features [15–18], resistance mechanisms remain understudied. Similarly, there is a lack of reliable biomarkers for the diagnosis, treatment and prognosis of this disease [19]. Our study established gemcitabine-resistant cell lines and identified the DNA helicase DDX11 as a potential resistance mediator through microarray analysis. As a genome stability regulator [20,21], DDX11 dysfunction may impair DNA repair, promoting chemoresistance, a novel finding that offers therapeutic insights.