A new emerging hallmark for many malignancies is altered metabolic direction to support rapid cell proliferation. Considerable progress has been made in elucidating how modified cell signaling contributes to deregulated cell growth in cancer, much less is known regarding metabolic rewiring to provide for the demand in building blocks to support the ever-increasing cell numbers. Within the last few years metabolite profiling between normal and cancer cells has provided new insights to uncover the underlying mechanisms of cellular transformation. Glutamine is the most abundant amino acid in blood and is recognized as a critical contributor in nearly every central metabolic task of proliferating tumor cells. Recently, glutamine was deemed as an essential component in mitochondrial metabolisms to ensure that rapidly growing tumor cells will remain metabolically versatile, particularly the reprogramming of the oxidative to reductive mitochondrial glutamine metabolism. Reductive glutamine metabolism has been shown to be preferred under hypoxia condition via the stabilization of the hypoxia-induced transcription factor 1? (HIF-1?). Our group demonstrated the etiological role of an ectopic expression of a murine neuronal receptor, metabotropic glutamate receptor 1 (GRM1) in mouse melanocytes in genetically modified transgenic mouse melanoma models. Aberrant expression of the human form of GRM1 was also observed in ?65% of human melanoma cell lines and biopsy samples but not normal human melanocytes, suggesting its involvement in melanomagenesis. Recently, we uncovered yet another consequence in cells with enhanced/aberrant GRM1 expression, upregulated HIF-1?. These preliminary results suggest there may be a link between altered glutamine metabolism and glutamatergic signaling mediated by aberrant GRM1 expression. We hypothesize that ectopic GRM1 expression in melanocytes results in deregulated cell proliferation, increase in HIF-1?, which participates in the rewiring of the metabolic networks that fuel the increasing demand for the synthesis of biological molecules required for cell growth.
The uncontrolled cell proliferation that represents the hallmark of neoplastic disease not only involves deregulated cell proliferation but also requires adjustments in the energy metabolism that fuels the cells growth particularly altered glutamine metabolisms. Our proposed studies will interrogate possible relationship between altered glutamatergic signaling and glutamine metabolisms in melanoma.
|Shin, Seung-Shick; Jeong, Byeong-Seon; Wall, Brian A et al. (2018) Participation of xCT in melanoma cell proliferation in vitro and tumorigenesis in vivo. Oncogenesis 7:86|