FoxM1 amplification in human pancreatic cancer predicts poor prognosis and resistance to paclitaxel. Here, a novel role between FoxM1 (FoxM1b and FoxM1c) and Prohibitin1 (PHB1) in paclitaxel resistance has been identified. We adopted a bioinformatics approach to predict the potential effector of FoxM1. It specifically bound to the promoter of PHB1, and it enhanced PHB1 expression at transcriptional and post-transcriptional levels. FoxM1 contributed to the PHB1/C-RAF interaction and phosphorylation of ERK1/2 kinases, thus promoting paclitaxel resistance. Notably, FoxM1 conferred tumor cell resistance to paclitaxel, but knocking down PHB1 could sensitize pancreatic cancer cells to it. Besides, we identified that ABCA2 promoted paclitaxel resistance under the regulation of FoxM1/PHB1/RAF-MEK-ERK. Thiostrepton, an inhibitor of FoxM1, significantly decreased the expression of PHB1, p-ERK1/2, and ABCA2. It increased the influx of paclitaxel into the cell, and it attenuated FoxM1-mediated paclitaxel resistance in vitro and in vivo. Collectively, our findings defined PHB1 as an important downstream effector of FoxM1. It was regulated by FoxM1 to maintain phosphorylation of ERK1/2 in drug-resistant cells, and FoxM1 simultaneously enhanced the function of ABCA2, which collectively contributed to paclitaxel resistance. Targeting FoxM1 and its downstream effector PHB1 increased the sensitivity of pancreatic cells to paclitaxel treatment, providing potential therapeutic strategies for patients with paclitaxel resistance.

人类胰腺癌中FoxM1的扩增预示着紫杉醇的不良预后和耐药性。在这里，已经确定了FoxM1（FoxM1b和FoxM1c）和Prohibitin1（PHB1）在紫杉醇耐药性中的新作用。我们采用了生物信息学方法来预测FoxM1的潜在效应。它与PHB1的启动子特异性结合，并在转录和转录后水平上增强了PHB1的表达。FoxM1有助于PHB1 / C-RAF相互作用和ERK1 / 2激酶的磷酸化，从而促进紫杉醇的耐药性。值得注意的是，FoxM1赋予肿瘤细胞对紫杉醇的抗性，但敲低PHB1可使胰腺癌细胞对其敏感。此外，我们发现ABCA2在FoxM1 / PHB1 / RAF-MEK-ERK的调控下促进了紫杉醇抗性。Thiostrepton，FoxM1的抑制剂，p -ERK1 / 2和ABCA2。它增加了紫杉醇向细胞内的流入，并在体外和体内减弱了FoxM1介导的紫杉醇耐药性。总的来说，我们的发现将PHB1定义为FoxM1的重要下游效应子。它受到FoxM1的调节，以维持耐药细胞中ERK1 / 2的磷酸化，而FoxM1同时增强了ABCA2的功能，共同促进了紫杉醇的耐药性。靶向FoxM1及其下游效应物PHB1提高了胰腺细胞对紫杉醇治疗的敏感性，为紫杉醇耐药的患者提供了潜在的治疗策略。