PDLIM1 Inhibits Chemoresistance by Blocking DNA Damage Repair in Gastric Cancer

Abstract

Objective: Current cisplatin (CDDP) resistance remains a major challenge in the treatment of advanced gastric cancer. To address the issue of drug resistance, we explored the regulatory functions of PDZ and LIM structural domain protein 1 (PDLIM1) in CDDP chemotherapy for gastric cancer. Methods: In this study, we analyzed PDLIM1 expression and prognosis using bioinformatics on publicly available data. PDLIM1 expression in a gastric mucosal epithelial cell line (GSE-1), CDDP- sensitive (SGC7901, BGC823) and CDDP-resistant gastric cancer cells was detected by RTqPCR and Western blotting. Cell proliferative capacity was assessed by knockdown of PDLIM1 and overexpression of PDLIM1 in cells administered in combination with cisplatin, and apoptotic levels were measured by CCK-8 and colony formation assay and by flow cytometry. Expression of breast cancer susceptibility gene 1 (BRCA1) and γH2AX was determined by Western blotting or immunofluorescence staining. Results: Downregulation of PDLIM1 was found in tumor tissues and cells, which was associated with poor clinical outcomes. Knockdown of PDLIM1 enhanced proliferation and attenuated apoptosis in gastric cancer cells. In addition, the therapeutic effects of CDDP on proliferation, apoptosis, and DNA damage repair were attenuated by PDLIM1 deletion.PDLIM1 expression was downregulated in CDDP-resistant tumor cells. Overexpression of PDLIM1 overcomes CDDP resistance in tumor cells as BRCA1 expression decreases and γH2AX expression increases. Conclusion: Our findings demonstrate that PDLIM1 enables to alleviate gastric cancer progression and resistance to cisplatin via impeding DNA damage repair.