Amino Acid Signature in Human Melanoma Cell Lines from Different Disease Stages

Abstract

Cancer cells rewire metabolism to sustain high proliferation rates. Beside glycolysis and glutaminolysis, amino acids substitute as energy source, feed fatty acid biosynthesis and represent part of the secretome of transformed cells, including melanoma. We have therefore investigated acetate, pyruvate and the amino acid composition of the secretome of human melanoma cells representing the early slow (WM35, WM278, WM793b and VM21) and metastatic fast (A375, 518a2, 6F and WM8) growth phase in order to identify possible signalling components within these profiles. Proliferation assays and a principle component analysis revealed a stringent difference between the fast and slow growing melanoma cells. Moreover, upon inhibition of the mevalonate pathway, glutamic acid and alanine were identified as the central difference in the conditional media. A supplementation of the media with glutamic acid and the combination with alanine significantly accelerated the proliferation, migration and invasion of early stage melanoma cells, but not metastatic cells. Finally, the inhibition of the mevalonate pathway abolished the growth advantage of the melanoma cells in a time dependent manner. Taken together, these data corroborate a stage specific response in growth and aggressiveness to extracellular glutamic acid and alanine, indicative for microenvironmental signalling of individual amino acids.

Autocrine/paracrine actions of growth hormone in human melanoma cell lines

“…We first examined melanoma cell GH signaling in the human WM35 cell line, which was established from a primary superficial spreading melanoma in radial/vertical growth phase [22]. Cells were treated with GH (500 ng/mL) for 0, 2, 5, 10, 15, 30 or 60min.…”

Targeted Metabolomics Identifies Plasma Biomarkers in Mice with Metabolically Heterogeneous Melanoma Xenografts

“…Metabolic heterogeneity between melanoma subtypes was also reflected by significant alterations in beta-alanine, alanine, aspartate, glutamate, as well as histidine metabolism. In a previous study, altered glutamate and alanine levels were identified as the main differences in conditioned media of cell cultures of early-stage non-metastatic and metastatic melanoma cells, indicating a stage-specific requirement for glutamate and alanine for growth and aggressiveness [ 78 ]. Changes in alanine, aspartate, glutamate, as well as beta-alanine metabolism were recently associated with melanoma development [ 43 ].…”

Blood glutamate scavengers increase pro-apoptotic signaling and reduce metastatic melanoma growth in-vivo

“…Tumor cells release Glu mainly via the xc− antiporter, a transporter that plays a critical role in maintaining intracellular and extracellular antioxidant levels (e.g., glutathione, cysteine) by exchanging extracellular cystine for intracellular glutamate 6 , 63 . Excess extracellular Glu has been shown to enhance glioma and melanoma tumor cell growth and invasion 1 , 63 – 66 , and studies have demonstrated that inhibiting the release of Glu results in a decrease of melanoma tumor growth in mGlu1 receptor-expressing melanomas 63 , 67 . Similarly, our results demonstrate that reducing extracellular Glu levels following BGS treatment inhibits tumor cell proliferation and induces apoptotic tumor cell death.…”