| 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
|
| Resource |
| Human and Animal Cells |
MKN74(RCB1002) |
