Low-dose YC-1 combined with glucose and insulin selectively induces apoptosis in hypoxic gastric carcinoma cells by inhibiting anaerobic glycolysis.

ABSTRACT: This study aimed to establish a therapeutic strategy targeting hypoxic cancer cells in gastric carcinoma (GC). YC-1 is a HIF-1? inhibitor, and we revealed that low-dose YC-1 (10?µM) suppressed HIF-1? expression, and induced hypoxia-dependent apoptosis in the GC cell line 58As9. This hypoxia-specific apoptosis induction by YC-1 involved excessive reactive oxygen species (ROS) generation. The apoptotic effect of 10?µM YC-1 was enhanced by additional glucose (G) and insulin (I) treatments. RT-PCR demonstrated that 10?µM YC-1 reduced hypoxia-induced expression of HIF-1? targets involved in anaerobic glycolysis. Metabolic analysis showed that YC-1 shifted glucose metabolism in hypoxic cells from anaerobic glycolysis to oxidative phosphorylation (OXPHOS). Additional GI accelerated membranous GLUT1 translocation, elevating glucose uptake, and increased acetyl-CoA levels, leading to more ROS generation in hypoxic YC-1-treated cells. Finally, we evaluated the anti-cancer effect of low-dose YC-1 (1?mg/kg)?+?G (2?g/kg) and I (1 unit/3?g?G) treatment in xenograft models. YC-1?+?GI therapy strongly inhibited tumour growth. Immunohistochemical analysis demonstrated that YC-1?+?GI reduced HIF-1? expression and pimonidazole accumulation in tumours. Conversely, YC-1?+?GI increased intra-tumoral 8-OHdG and levels of apoptosis markers. Low-dose YC-1?+?GI is a unique therapy targeting hypoxic GC cells that generates lethal ROS via forced activation of OXPHOS.

SUBMITTER: Wakiyama K 

PROVIDER: S-EPMC5627264 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature