Key Takeaways & Executive Findings
- •• KIF5A is highly expressed in LUAD and correlates with glycolysis-related genes, promoting docetaxel resistance. • Silencing KIF5A inhibits glycolysis, lactate production, and DTX resistance in LUAD cells. • FOXP3 transcriptionally activates KIF5A, and its knockdown reduces lactate production and enhances DTX sensitivity. • The FOXP3-KIF5A-lactic acid axis offers a novel therapeutic target to improve chemosensitivity in LUAD.
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.
1. Introduction
Lung cancer is the most common malignant tumor and a significant factor in cancer-related mortality worldwide. The most predominant kind of lung cancer is non-small cell lung cancer (NSCLC). In many nations during the past 2 decades, lung adenocarcinoma (LUAD), which accounts for approximately 40% of patients, has emerged as the most prevalent subtype of NSCLC. Despite its high proliferative capacity and aggressive nature, the treatment outcomes and prognosis for LUAD patients remain unsatisfactory. Chemotherapy remains a prevalent treatment modality for LUAD, primarily in patients with advanced stages or resistance to targeted therapies or immunotherapies.
Docetaxel (DTX), a broad-spectrum anticancer chemotherapy drug, exerts its antitumor effects primarily by disrupting the cell cycle of tumor cells. Its mechanism is similar to that of paclitaxel, but it exhibits higher intracellular concentration and prolonged action. When DTX enters the cell, it interacts with microtubule proteins to cause microtubule polymerization and the formation of non-functioning microtubules. This impairs spindle function, impedes tumor cell mitosis, and eventually stops tumor cell proliferation. However, due to the aggressive behavior of LUAD tumors, patients undergoing DTX treatment often develop resistance or relapse. Therefore, a thorough understanding of the potential mechanisms underlying DTX resistance is of great significance for clinical drug selection and rational use.
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Liangliang Dong, Chan Feng, Wenwen Cheng, Aihua Huang, Kejing Ying (2026). FOXP3 targets KIF5A to increase lactate production and promote docetaxel resistance in lung adenocarcinoma. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024082
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Frequently Asked Questions
What is the role of KIF5A in lung adenocarcinoma?
KIF5A is highly expressed in LUAD and is associated with poor prognosis. It promotes docetaxel resistance by enhancing glycolysis and lactate production.
How does FOXP3 regulate KIF5A expression?
FOXP3 transcriptionally activates KIF5A by binding to its promoter, as demonstrated by chromatin immunoprecipitation and dual-luciferase reporter assays.
What is the significance of lactate production in docetaxel resistance?
Lactate production, a hallmark of the Warburg effect, contributes to chemoresistance. In LUAD, increased lactate production via KIF5A upregulation promotes DTX resistance.
Can targeting the FOXP3-KIF5A axis improve chemotherapy outcomes?
Yes, inhibiting FOXP3 or KIF5A reduces lactate production and enhances DTX sensitivity, suggesting a novel therapeutic strategy to overcome chemoresistance in LUAD.
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