ALDH2 inhibits angiogenesis in esophageal squamous cell carcinoma by suppressing the NOTCH1/PI3K/Akt signaling pathway.

Abstract

Esophageal Squamous Cell Carcinoma (ESCC) stands as the predominant form of esophageal cancer globally, bearing high morbidity and mortality rates attributed to its capacity for infiltration and metastasis. Angiogenesis emerges as a pivotal factor influencing ESCC progression. To explore how to modulate angiogenesis for anti-ESCC therapy effectively, here we evaluated the potential of acetaldehyde dehydrogenase 2 (ALDH2) as a targeted therapy for ESCC and elucidated the molecular mechanisms by which ALDH2 inhibits ESCC angiogenesis. Our findings reveal a correlation between low ALDH2 expression and the progression as well as poor prognosis of ESCC. Additionally, ESCC cell apoptosis was stimulated while ESCC cell proliferation, migration, invasion, and angiogenesis were all successfully suppressed by ALDH2 overexpression. Regarding the molecular mechanism, ALDH2 was observed to suppress NOTCH1, which in turn inhibited the PI3K/Akt pathway, thereby hindering the expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGFA), which are both linked to angiogenesis, and ultimately exerting its inhibitory effect on ESCC through this regulatory cascade. Importantly, we established a subcutaneous xenograft tumor model in BALB/c nude mice using ESCC cell lines with ALDH2 overexpression. Our results demonstrated that ALDH2 overexpression significantly inhibited tumor growth and angiogenesis, further supporting ALDH2 as a potential therapeutic target in ESCC. Finally, we screened Tectoridin (TEC), an agonist of ALDH2, and demonstrated its ability to inhibit ESCC. These findings provide an empirical basis for the development of novel therapeutic strategies for ESCC.