Enhanced OXPHOS, glutaminolysis and beta-oxidation constitute the metastatic phenotype of melanoma cells

Enhanced OXPHOS, glutaminolysis and beta-oxidation constitute the metastatic phenotype of melanoma cells

Author Rodrigues, Mariana F. Google Scholar
Obre, Emilie Google Scholar
de Melo, Fabiana H. M. Autor UNIFESP Google Scholar
Santos, Gilson C., Jr. Google Scholar
Galina, Antonio Google Scholar
Jasiulionis, Miriam G. Autor UNIFESP Google Scholar
Rossignol, Rodrigue Google Scholar
Rumjanek, Franklin D. Google Scholar
Amoedo, Nivea D. Google Scholar
Abstract Tumours display different cell populations with distinct metabolic phenotypes. Thus, subpopulations can adjust to different environments, particularly with regard to oxygen and nutrient availability. Our results indicate that progression to metastasis requires mitochondrial function. Our research, centered on cell lines that display increasing degrees of malignancy, focused on metabolic events, especially those involving mitochondria, which could reveal which stages are mechanistically associated with metastasis. Melanocytes were subjected to several cycles of adhesion impairment, producing stable cell lines exhibiting phenotypes representing a progression from non-tumorigenic to metastatic cells. Metastatic cells (4C11+) released the highest amounts of lactate, part of which was derived from glutamine catabolism. The 4C11+ cells also displayed an increased oxidative metabolism, accompanied by enhanced rates of oxygen consumption coupled to ATP synthesis. Enhanced mitochondrial function could not be explained by an increase in mitochondrial content or mitochondrial biogenesis. Furthermore, 4C11+ cells had a higher ATP content, and increased succinate oxidation (complex II activity) and fatty acid oxidation. In addition, 4C11+ cells exhibited a 2-fold increase in mitochondrial membrane potential (Lambda psi(mit])). Consistently, functional assays showed that the migration of cells depended on glutaminase activity. Metabolomic analysis revealed that 4C11+ cells could be grouped as a subpopulation with a profile that was quite distinct from the other cells investigated in the present study. The results presented here have centred on how the multiple metabolic inputs of tumour cells may converge to compose the so-called metastatic phenotype.
Keywords energy metabolism
metastasis
mitochondrial physiology
OXPHOS
xmlui.dri2xhtml.METS-1.0.item-coverage London
Language English
Sponsor CAPES-COFECUB
CNPq
FAPERJ
FAF
INCT/CNPq-Cancer
Grant number CAPES-COFECUB: 798-14
FAPERJ : -26/103.002/2011
FAPERJ: E26/102.231/2013
Date 2016
Published in Biochemical Journal. London, v. 473, p. 703-715, 2016.
ISSN 0264-6021 (Sherpa/Romeo, impact factor)
Publisher Portland Press Ltd
Extent 703-715
Origin http://dx.doi.org/10.1042/BJ20150645
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000377208100005
URI https://repositorio.unifesp.br/handle/11600/57783

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