RRC ID 65118
Author Wakiyama K, Kitajima Y, Tanaka T, Kaneki M, Yanagihara K, Aishima S, Nakamura J, Noshiro H.
Title Low-dose YC-1 combined with glucose and insulin selectively induces apoptosis in hypoxic gastric carcinoma cells by inhibiting anaerobic glycolysis.
Journal Sci Rep
Abstract This study aimed to establish a therapeutic strategy targeting hypoxic cancer cells in gastric carcinoma (GC). YC-1 is a HIF-1α inhibitor, and we revealed that low-dose YC-1 (10 µM) suppressed HIF-1α 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-1α 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-1α 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.
Volume 7(1)
Pages 12653
Published 2017-10-4
DOI 10.1038/s41598-017-12929-9
PII 10.1038/s41598-017-12929-9
PMID 28978999
PMC PMC5627264
MeSH 8-Hydroxy-2'-Deoxyguanosine Acetyl Coenzyme A / genetics Anaerobiosis / drug effects Animals Apoptosis / drug effects Carcinoma / drug therapy* Carcinoma / metabolism Carcinoma / pathology Cell Line, Tumor Deoxyguanosine / administration & dosage Deoxyguanosine / analogs & derivatives Glucose / metabolism Glucose Transporter Type 1 / genetics* Glycolysis / drug effects Humans Hypoxia-Inducible Factor 1, alpha Subunit / genetics* Indazoles / administration & dosage* Insulin / metabolism Mice Nitroimidazoles / administration & dosage Oxidative Phosphorylation / drug effects Stomach Neoplasms / drug therapy* Stomach Neoplasms / metabolism Stomach Neoplasms / pathology Tumor Hypoxia Xenograft Model Antitumor Assays
IF 3.998
Human and Animal Cells MKN74(RCB1002)