HMTA, a natural alkylphenol from Ardisia virens Kurz, obstructs autophagic flux to exert anti-pancreatic cancer activity.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies worldwide due to its aggressive nature and limited therapeutic options. HMTA (4-hydroxy-2-methoxy-6-tridecylphenyl acetate), a natural alkylphenol derived from Ardisia virens Kurz, has previously demonstrated anti-tumor potential as a tubulin polymerization inhibitor. However, its impact on the autophagic machinery in pancreatic cancer remains to be elucidated. In this study, we investigated the anti-cancer effects of HMTA across four human pancreatic cancer cell lines (PANC-1, BxPC-3, MIA PaCa-2, and AsPC-1) with varying KRAS mutation statuses. HMTA significantly inhibited cell viability in a dose-dependent manner. Mechanistically, HMTA treatment led to a substantial accumulation of LC3-II and p62/SQSTM1 proteins. Notably, the expression of upstream autophagy-initiating markers, such as ATG5 and Beclin-1, remained unchanged, suggesting a defect in autophagic clearance rather than induction. Using a tandem mRFP-EGFP-LC3 fluorescence reporter assay, we found that HMTA obstructs autophagic flux by preventing the fusion of autophagosomes with lysosomes. Furthermore, the combination of HMTA with the autophagy inhibitor chloroquine resulted in enhanced cytotoxicity, whereas the early-stage inhibitor 3-MA partially rescued HMTA-induced cell death. Our findings demonstrate that HMTA exerts its anti-pancreatic cancer activity mainly through the blockade of autophagic flux, regardless of KRAS background. These results position HMTA as a promising therapeutic candidate for the treatment of PDAC.