Elevated NDRG1 Expression Drives Oxaliplatin Chemoresistance in Bladder Cancer Cells by Promoting Homologous Recombination Repair and Inhibiting G

Long-term oxaliplatin treatment frequently leads to chemoresistance in specific cancers, including bladder cancer, although the underlying mechanisms remain incompletely characterized. Bladder cancer cell line 5637 was rendered stably resistant to oxaliplatin via prolonged exposure to increasing concentrations. Following this, transcriptomic analysis identified N-myc downstream regulated gene-1 (NDRG1) as a candidate resistance mediator. Functional studies using NDRG1-targeted siRNA and overexpression plasmids were then conducted to assess cell viability, apoptosis, cell cycle distribution, homologous recombination (HR) activity, expression of cell cycle and DNA damage repair proteins, and DNA double-strand break (DSB) formation. NDRG1 expression was significantly elevated in resistant cells and promoted chemoresistance through dual mechanisms: enhancing G2/M progression via cyclin-dependent kinase 1 (CDK1) /cyclin B1 upregulation and facilitating HR-mediated repair through increased phosphorylation of Nijmegen breakage syndrome 1 (NBS1) and breast cancer susceptibility gene 1 (BRCA1), and elevated expression of Rad51 and Rad54. Consequently, HR activity was amplified and DSB accumulation reduced. Inhibition of NDRG1, CDK1, BRCA1, or Rad51 restored oxaliplatin sensitivity by reducing cell viability and promoting apoptosis. Functional studies demonstrated that CDK1 is a critical downstream effector by showing that its overexpression restored oxaliplatin resistance in NDRG1-silenced cells and its inhibition attenuated NDRG1-driven BRCA1 phosphorylation. Our study identifies a novel NDRG1-coordinated mechanism that promotes chemoresistance through dual regulation of cell cycle progression and HR repair, nominating the NDRG1-centered signaling network as a promising target for reversing platinum resistance.