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.
吉西他滨（GEM）化疗耐药性的发展严重限制了其在胰腺癌（PC）中的治疗效果，而铁死亡失调是化疗耐药性发展的关键因素。BUB1有丝分裂检查点丝氨酸/苏氨酸激酶（BUB1）在PC患者中高度过表达，且与患者预后密切相关。然而，目前尚无文献报道BUB1与铁死亡之间的关联，GEM耐药的分子机制也尚未明确。因此，本研究首先确认了BUB1在PC患者中的高表达水平，进而探究BUB1在铁死亡过程中的作用，最终揭示了BUB1通过调控铁死亡促进PC细胞GEM耐药的具体机制。本研究发现，下调BUB1可增强PC细胞对Erastin的敏感性，并抑制细胞增殖与迁移。机制上，BUB1能够抑制神经纤维蛋白2（NF2）和MOB激酶激活因子1（MOB1）的表达水平，并促进Yes相关蛋白（YAP）的表达，从而抑制铁死亡并促进PC细胞的GEM耐药。此外，BUB1抑制与GEM联合使用表现出协同治疗效果。这些发现揭示了基于铁死亡的GEM化疗耐药发展机制，并提示联合使用BUB1抑制剂可能是增强GEM疗效的有效策略。
BUB1 Promotes Gemcitabine Resistance in Pancreatic Cancer Cells by Inhibiting Ferroptosis
肿瘤(癌症)患者之家