Celecoxib inhibits COX-2 and initiates YAP-dependent mitochondrial apoptosis via YBX1 shuttling in hepatocellular carcinoma

Drug resistance poses a significant challenge in hepatocellular carcinoma (HCC) treatment. In this study, we aimed to assess the efficacy of celecoxib against HCC and uncover the underlying mechanism. Through rigorous drug screening on diverse HCC cell lines and cell line-derived xenografts, we investigated the anti-HCC potential of celecoxib. Utilizing advanced techniques such as RNA-sequencing, proteomics assays, co-immunoprecipitation, and ChIP-PCR, we explored the intricate molecular processes leading to the nucleocytoplasmic shuttling of the YAP-YBX1 complex in celecoxib-induced HCC cell death. Celecoxib unambiguously exhibited an antitumor effect on HCC cells through downregulating COX-2 to induce mitochondrial apoptosis. Mechanistically, celecoxib turned off the Hippo pathway to initiate the nuclear translocation of YAP, which led to the nucleocytoplasmic shuttling of YBX1 and suppressed its transcription role on PTGS2 (encoding COX-2). Notably, blocking YAP resulted in diminished nuclear accumulation of YBX1, affording survival to HCC cells exposed to celecoxib. Our findings highlighted the pivotal role of the nucleocytoplasmic shuttling of YBX1-YAP complex in the celecoxib-induced HCC cells death, repressing the transcription of PTGS2 and contributing to mitochondrial apoptosis of HCC cells. Schematic diagram of celecoxib induced mitochondrial apoptosis in HCC cells. A Celecoxib inhibited the growth of HCC cells. B Celecoxib induced mitochondrial apoptosis by downregulating the expression of COX-2 in HCC cells. C Celecoxib turned off Hippo pathway to promote the nuclear translocation of YAP, which contributes to nucleocytoplasmic shuttling of YBX1, resulting in downregulating the transcriptional function of YBX1 on PTGS2 and repressing COX-2 expression