Department of Respiratory and Critical Care Medicine, Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310020, China.
Department of Education Office, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310020, China.
Acta Biochim Biophys Sin (Shanghai). 2024 May 26;56(7):1011-1021. doi: 10.3724/abbs.2024082.
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 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 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.
一个突出的与预后不良相关的癌症死亡原因是肺腺癌（LUAD）。驱动蛋白家族的重要成员 KIF5A 与恶性肿瘤的耐药性有关。这项工作旨在研究 KIF5A 在 LUAD 细胞中对多西紫杉醇（DTX）耐药的机制。生物信息学分析、qRT-PCR 和 Western blot 分析的结果表明，参与糖酵解途径的 KIF5A 在 LUAD 中高表达，并且与糖酵解相关基因呈正相关。我们进一步验证，通过细胞计数试剂盒-8（CCK-8）、流式细胞术、 Seahorse XFe 96、乳酸和葡萄糖测定，沉默 KIF5A 可抑制 LUAD 细胞中的 DTX 耐药性、糖酵解和乳酸生成。在机制上，KIF5A 促进 LUAD 中的 DTX 耐药性，而添加 LDHA 抑制剂可减弱这种作用。染色质免疫沉淀和双荧光素酶报告基因检测显示，FOXP3 转录激活 KIF5A。 沉默 可减少 LUAD 中的乳酸生成并提高 DTX 敏感性，而同时过表达 KIF5A 则可恢复。我们的研究结果表明，FOXP3 通过上调 KIF5A 水平增加乳酸生成从而增加 LUAD 细胞的 DTX 耐药性。总之，我们的研究为提高 LUAD 的化疗敏感性提供了一个新的治疗靶点。
