Alda‑1 restores ALDH2‑mediated alcohol metabolism to inhibit the NF‑κB/VEGFC axis in head and neck cancer.

Abstract

The adaptation of cancer cells to hostile environments often necessitates metabolic pathway alterations to sustain proliferation and invasion. Head and neck cancer (HNC) has unfavorable outcomes. Therefore, elucidating the functional effects and molecular mechanisms underlying metabolic changes is key. Ingenuity Pathway Analysis identified 'ethanol degradation pathway II and IV' was consistently downregulated in tumor tissue, with aldehyde dehydrogenase 2 (ALDH2) emerging as a key prognostic gene among the top‑ranked differentially expressed metabolic pathways. Immunohistochemistry (IHC) of HNC specimens revealed significant downregulation of ALDH2 expression in tumor tissue, which was inversely correlated with T classification, overall stage, recurrence rate and independently predicted poor prognosis. Functional assays showed that ALDH2 knockdown enhanced HNC cell migration, invasion and colony formation, while ALDH2 overexpression attenuated these processes. Mechanistically, ALDH2 downregulation and subsequent reactive oxygen species (ROS) production in cells activated NF‑κB, upregulating vascular endothelial growth factor C (VEGFC) expression. ALDH2 overexpression inhibited ROS production and the NF‑κB/VEGFC oncogenic pathway, with pharmacological inhibition of NF‑κB and VEGFC mitigating the enhanced migration and invasion of ALDH2‑knockdown HNC cells. IHC and transcriptome analysis further highlighted an inverse association between ALDH2 and VEGFC, with the ALDH2^high/VEGFC^low profile predicting the most favorable survival outcome. Inhibition of ALDH2 with Daidzin increased VEGFC and phosphorylated NF‑κB levels, restoring the migration and invasion of ALDH2‑overexpressing HNC cells by enhancing the effects of VEGFC. Notably, modulating ALDH2 activity using Alda‑1 ameliorated NF‑kB/VEGFC axis upregulation following acetaldehyde treatment, aligning with the aforementioned alterations in alcohol metabolisms. These findings emphasize the key role of ALDH2 in influencing HNC progression and patient outcome, suggesting that targeting the ALDH2/NF‑κB/VEGFC pathway may represent a potential therapeutic strategy for HNC.