A Novel Autophagy Inhibitor p-Hydroxylcinnamaldehyde Suppresses Esophageal Squamous Cell Carcinoma by Targeting LDHA...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Autophagy and glucose metabolism are crucial for esophageal squamous cell carcinoma (ESCC) proliferation.
• Targeting both processes simultaneously presents a therapeutic opportunity for ESCC.
• Few anticancer drugs currently address both autophagy and glucose metabolism.

Purpose of the Study:

• To identify and evaluate a natural compound for its potential to target both autophagy and glucose metabolism in ESCC.
• To elucidate the mechanism by which this compound inhibits ESCC growth.
• To assess the in vitro and in vivo efficacy of the compound in ESCC models.

Main Methods:

• Identification of p-hydroxylcinnamaldehyde (CMSP) from Cochinchina momordica seed.
• In vitro studies using ESCC cell lines and patient-derived organoid (PDO) models.
• In vivo studies in animal models of ESCC.
• Mechanistic studies involving enzyme binding assays, phosphorylation analysis, and pathway analysis (AMPK/mTOR).

Main Results:

• CMSP demonstrated significant anticancer activity against ESCC in vitro and in vivo.
• CMSP disrupts autophagic flux by inhibiting the glycolytic enzyme lactate dehydrogenase A (LDHA).
• CMSP blocks LDHA phosphorylation, reduces lactate production, decreases lysosomal acidity, and suppresses the AMPK/mTOR pathway, leading to apoptosis.

Conclusions:

• CMSP is a novel natural compound with potent anticancer effects against ESCC.
• CMSP acts by simultaneously targeting glycolysis and autophagy through LDHA inhibition.
• CMSP represents a promising therapeutic strategy for the precision treatment of ESCC by targeting glycolysis-mediated autophagy.