Cisplatin (CDDP)-based systematic chemotherapy remains the mainstay of treatment for muscle-invasive bladder cancer (MIBC). However, acquired resistance to CDDP, a multifactorial process governed by an array of signals acting at different levels, is the major problem in BC treatment. Here, we report for the first time that, expression of Paired-box gene 5 (PAX5), a B-cell essential transcription factor, was significantly induced in CDDP-resistant BC tissues and in experimentally-induced CDDP-resistant BC cells. Inhibition of PAX5 expression by shRNA treatment effectively improved CDDP sensitivity in BC cells, whereas overexpression of PAX5 potentiated CDDP resistance through supporting BC cell survival. Mechanistically, using luciferase reporter and chromatin immunoprecipitation assays, we identified prostaglandin-endoperoxide synthase 2 (PTGS2, also called COX2), a potent enzyme responsible for prostanoids formation and inflammatory response, as the direct down-stream target of PAX5. PAX5 exerted its oncogenic function during the pathogenesis of CDDP resistance via stimulation of PTGS2 transcription. These observations collectively suggest that dysregulation of PAX5/PTGS2 cascade plays a causal role in the induction of CDDP resistance and gene silencing approaches targeting this pathway may therefore provide a novel therapeutic strategy for overcoming CDDP resistance in BC. (C) 2018 Elsevier Inc. All rights reserved.