BUB1 Promotes Gemcitabine Resistance in Pancreatic Cancer Cells by Inhibiting Ferroptosis.

Simple Summary: Further investigation into the molecular mechanisms of chemotherapy resistance in pancreatic cancer is crucial for improving the prognosis of pancreatic cancer patients. Extensive research has demonstrated a close association between ferroptosis and gemcitabine resistance in various tumor types, including pancreatic cancer. We first show that high expression of Mitotic checkpoint serine/threonine kinase BUB1 in pancreatic cancer and its association with poor prognosis. Results also suggested that BUB1 suppresses ferroptosis in pancreatic cancer cells, and BUB1 knockdown significantly enhances the sensitivity of drug-resistant pancreatic cancer cells to ferroptosis. Furthermore, BUB1 promotes gemcitabine resistance in pancreatic cancer cells. We believe that our study makes a significant contribution to the literature because it was previously unclear whether BUB1 plays a key role in pancreatic cancer ferroptosis. The development of chemotherapy resistance severely limits the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer (PC), and the dysregulation of ferroptosis is a crucial factor in the development of chemotherapy resistance. BUB1 Mitotic Checkpoint Serine/Threonine Kinase (BUB1) is highly overexpressed in PC patients and is closely associated with patient prognosis. However, none of the literature reports the connection between BUB1 and ferroptosis. The molecular mechanisms underlying GEM resistance are also not well understood. Therefore, this study first established the high expression levels of BUB1 in PC patients, then explored the role of BUB1 in the process of ferroptosis, and finally investigated the mechanisms by which BUB1 regulates ferroptosis and contributes to GEM resistance in PC cells. In this study, downregulation of BUB1 enhanced the sensitivity of PC cells to Erastin, and inhibited cell proliferation and migration. Mechanistically, BUB1 could inhibit the expression levels of Neurofibromin 2 (NF2) and MOB kinase activator 1 (MOB1), and promote Yes-associated protein (YAP) expression, thereby inhibiting ferroptosis and promoting GEM resistance in PC cells. Furthermore, the combination of BUB1 inhibition with GEM exhibited a synergistic therapeutic effect. These findings reveal the mechanisms underlying the development of GEM chemotherapy resistance based on ferroptosis and suggest that the combined use of BUB1 inhibitors may be an effective approach to enhance GEM efficacy. [ABSTRACT FROM AUTHOR]

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