Targeting glutamate metabolism in melanoma
The glutamate metabotropic receptor 1 (GRM1) drives oncogenesis when aberrantly activated in melanoma and several other cancers. Metabolomics reveals that patient-derived xenografts with GRM1-positive melanoma tumors exhibit elevated plasma glutamate levels associated with metastatic melanoma in vivo. Stable isotope tracing and GCMS analysis determined that cells expressing GRM1 fuel a substantial fraction of glutamate from glycolytic carbon. Stimulation of GRM1 by glutamate leads to activation of mitogenic signaling pathways, which in turn increases the production of glutamate, fueling autocrine feedback. Implementing a rational drug-targeting strategy, we critically evaluate metabolic bottlenecks in vitro and in vivo. Combined inhibition of glutamate secretion and biosynthesis is an effective rational drug targeting strategy suppressing tumor growth and restricting tumor bioavailability of glutamate.
Code (0)
등록된 구현이 없습니다.
Similar Papers 제목 키워드 기반
Branched chain amino acids, an ''essential'' link between diet, clock and sleep?
The branched-chain amino acids: leucine, isoleucine and valine occupy a special place among the essential amino acids because of their importance not only in the structure of proteins but also in general and cerebral met…
Towards decoding the coupled decision-making of metabolism and epithelial-mesenchymal transition in cancer
Cancer cells have the plasticity to adjust their metabolic phenotypes for survival and metastasis. During metastasis, a developmental program known as the epithelial-mesenchymal transition (EMT) plays a critical role. Th…
Decision MakingA Novel Bis-Coumarin Targets Multiple Tyrosine Kinases of Key Signaling Pathways in Melanoma and Inhibits Melanoma Cell Survival, Proliferation, and Migration
Melanoma is one of the most dangerous skin malignancies due to its high metastatic tendency and high mortality. Activation of key signaling pathways enforcing melanoma progression depends on phosphorylation of tyrosine k…
P53 Orchestrates Cancer Metabolism: Unveiling Strategies to Reverse the Warburg Effect
Cancer cells exhibit significant alterations in their metabolism, characterised by a reduction in oxidative phosphorylation (OXPHOS) and an increased reliance on glycolysis, even in the presence of oxygen. This metabolic…
A computational study on synaptic and extrasynaptic effects of astrocyte glutamate uptake on orientation tuning in V1
Astrocytes affect neural transmission by a tight control via glutamate transporters on glutamate concentrations in direct vicinity to the synaptic cleft and by extracellular glutamate. Their relevance for information rep…
Blocking