c-Myc-driven glycolysis via TXNIP suppression is dependent on glutaminase-MondoA axis in prostate cancer
| Autor: | Yami Zhang, Kai Li, Junbi Hu, Xuan Qu, Lei Gao, Jing Sun, Jun Li, Liangliang Shen |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Glucose uptake Prostatic Hyperplasia Biophysics Regulator Biochemistry Proto-Oncogene Proteins c-myc 03 medical and health sciences Glutaminase Humans Glycolysis Molecular Biology Psychological repression Principal Component Analysis Glutaminolysis Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Chemistry Gene Expression Profiling Prostatic Neoplasms Cell Biology Cell biology Gene Expression Regulation Neoplastic Phenotype 030104 developmental biology Anaerobic glycolysis Ketoglutaric Acids Carrier Proteins TXNIP |
| Zdroj: | Biochemical and Biophysical Research Communications. 504:415-421 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2018.08.069 |
| Popis: | Oncogenic c-Myc-induced metabolic reprogramming triggers cellular dependency on exogenous glucose and glutamine. Understanding how nutrients are used may provide new target for therapeutic intervention. We previously provided an alternate route to c-Myc-driven glucose metabolism via the repression of thioredoxin-interacting protein (TXNIP), which is a potent negative regulator of glucose uptake. Herein, we demonstrate that c-Myc suppression of TXNIP is predominantly through the activation of glutaminolysis via glutaminase (GLS1) in prostate cancer cells. Glutamine depletion blocked c-Myc-dependent reductions of TXNIP and its principal regulator MondoA transcriptional activity. Further, GLS1 inhibition by either siRNA or CB-839 resumed TXNIP expression that was repressed by c-Myc. The TXNIP promoter with mutant E-Box region, which was recognized by MondoA, failed to respond to c-Myc or GLS1, indicating c-Myc repression of TXNIP by GLS1 is predominantly through the blockage of MondoA activity. Especially, ectopic TXNIP expression decreased c-Myc-induce glucose uptake and lead to a broad range of glycolytic target gene suppressions. Thus TXNIP is a key adaptor for c-Myc-driven aerobic glycolysis. Supporting the biological significance of c-Myc and TXNIP, their reciprocal relationship are correlates with patient outcome and contributes to the aggressive phenotype in PCAs. |
| Databáze: | OpenAIRE |
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