Galectin-1 modulates glycolysis via a GM1-galactose-dependent pathway to promote hyperthermia resistance in hepatocellular carcinoma.

Abstract

BACKGROUND AND AIMS Thermal ablation is the standard of care treatment modality with curative intent for early-stage non-resectable hepatocellular carcinoma (HCC), but a durable response is limited-with up to 40% of HCC patients eventually experiencing local recurrence on post-treatment surveillance. While thermal ablation has been established to cause immediate cell death in the center of the thermal ablation zone, its metabolic impact in the peri-ablational region remains unclear. We aimed to elucidate the metabolic mechanism by which Galectin-1 (Gal-1) promotes thermal-ablation-induced hyperthermia resistance in HCC and demonstrate the therapeutic potential of inhibiting Gal-1 in combination with thermal ablation in vivo. APPROACH AND RESULTS Proteomic analysis was performed using an untargeted approach on pre-ablation formalin-fixed paraffin-embedded (FFPE) biopsy specimens of thermal ablation responders (n=32) and nonresponders (n=23). Gal-1 was found to be overexpressed in thermal ablation nonresponders compared to responders. Moreover, HCC with Gal-1 overexpression demonstrated reduced sensitivity to hyperthermia in vitro and increased utilization of glycolysis and downstream TCA cycle under hyperthermia-induced stress. Gal-1-overexpressing HCC enhanced its metabolic utilization through Gal-1-facilitated GM1-ganglioside breakdown, producing galactose to increase the metabolic influxes into glycolysis and consequently the downstream TCA cycle. In vivo studies showed that inhibiting Gal-1 in combination with thermal ablation significantly reduced tumor size compared to either monotherapy thermal ablation or Gal-1 inhibition alone. CONCLUSIONS Gal-1 can mediate hyperthermia resistance in HCC and can potentially be modulated as a therapeutic target to reduce rapid progression after thermal ablation.