PDF(Pubmed)
Abstract：
A prominent cause of cancer-related fatalities with a poor prognosis is lung adenocarcinoma (LUAD). KIF5A, a crucial member of the kinesin superfamily, is linked to drug resistance in malignancies. This work aims to investigate the mechanism of KIF5A in docetaxel (DTX) resistance in LUAD cells. The results of bioinformatics analysis, qRT-PCR and western blot analysis show that KIF5A, which is involved in the glycolysis pathway, is highly expressed in LUAD and is positively correlated with glycolysis-related genes. We further verify that silencing of KIF5A inhibits DTX resistance, glycolysis, and lactate production in LUAD cells via cell counting kit-8 (CCK-8), flow cytometry, Seahorse XFe 96, lactate, and glucose assays. Mechanistically, KIF5A promotes DTX resistance in LUAD, and this effect is attenuated upon the addition of an LDHA inhibitor. Chromatin immunoprecipitation and dual-luciferase reporter assays reveal that FOXP3 transcriptionally activates KIF5A. Knockdown of FOXP3 reduces lactate production and enhances DTX sensitivity in LUAD, which is restored upon simultaneous overexpression of KIF5A. Our findings reveal that FOXP3 increases DTX resistance in LUAD cells by enhancing lactate production through the upregulation of KIF5A level. In conclusion, our study provides a novel treatment target for improving chemosensitivity in LUAD.
摘要：
预后不良的癌症相关死亡的主要原因是肺腺癌（LUAD）。KIF5A,驱动蛋白超家族的重要成员，与恶性肿瘤的耐药性有关。本研究旨在探讨KIF5A在LUAD细胞多西他赛(DTX)耐药中的作用机制。生物信息学分析的结果，qRT-PCR和westernblot分析表明,KIF5A,参与糖酵解途径，在LUAD中高表达，并与糖酵解相关基因呈正相关。我们进一步验证KIF5A的沉默抑制DTX抗性，糖酵解,通过细胞计数试剂盒-8（CCK-8）在LUAD细胞中产生乳酸，流式细胞术,海马XFe96，乳酸，和葡萄糖测定。机械上,KIF5A促进LUAD的DTX抗性，并且这种效应在添加LDHA抑制剂时减弱。染色质免疫沉淀和双荧光素酶报告基因测定显示FOXP3转录激活KIF5A。敲除FOXP3可减少LUAD的乳酸产生并增强DTX敏感性，在同时过表达KIF5A后恢复。我们的发现表明，FOXP3通过上调KIF5A水平来增强乳酸的产生，从而增加了LUAD细胞中的DTX抗性。总之,我们的研究为改善LUAD的化疗敏感性提供了一个新的治疗靶点.
