title: Metabolic reprogramming supports the invasive phenotype in malignant melanoma.
abstract: Invasiveness is a hallmark of aggressive cancer like malignant melanoma, and factors involved in acquisition or maintenance of an invasive phenotype are attractive targets for therapy. We investigated melanoma phenotype modulation induced by the metastasis-promoting microenvironmental protein S100A4, focusing on the relationship between enhanced cellular motility, dedifferentiation and metabolic changes. In poorly motile, well-differentiated Melmet 5 cells, S100A4 stimulated migration, invasion and simultaneously down-regulated differentiation genes and modulated expression of metabolism genes. Metabolic studies confirmed suppressed mitochondrial respiration and activated glycolytic flux in the S100A4 stimulated cells, indicating a metabolic switch toward aerobic glycolysis, known as the Warburg effect. Reversal of the glycolytic switch by dichloracetate induced apoptosis and reduced cell growth, particularly in the S100A4 stimulated cells. This implies that cells with stimulated invasiveness get survival benefit from the glycolytic switch and, therefore, become more vulnerable to glycolysis inhibition. In conclusion, our data indicate that transition to the invasive phenotype in melanoma involves dedifferentiation and metabolic reprogramming from mitochondrial oxidation to glycolysis, which facilitates survival of the invasive cancer cells. Therapeutic strategies targeting the metabolic reprogramming may therefore be effective against the invasive phenotype.
authors.affiliation: Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Bettum
authors.affiliation: Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; St. Olavs University Hospital, Trondheim, Norway.
authors.forename: Saurabh S
authors.initials: SS
authors.lastname: Gorad
authors.affiliation: Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Anna
authors.initials: A
authors.lastname: Barkovskaya
authors.affiliation: Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Solveig
authors.initials: S
authors.lastname: Pettersen
authors.affiliation: Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; St. Olavs University Hospital, Trondheim, Norway.
authors.forename: Siver A
authors.initials: SA
authors.lastname: Moestue
authors.affiliation: Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Kotryna
authors.initials: K
authors.lastname: Vasiliauskaite
authors.affiliation: Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Ellen
authors.initials: E
authors.lastname: Tenstad
authors.affiliation: Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Tove
authors.initials: T
authors.lastname: Øyjord
authors.affiliation: Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; St. Olavs University Hospital, Trondheim, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Risa
authors.affiliation: Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Vigdis
authors.initials: V
authors.lastname: Nygaard
authors.affiliation: Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
authors.forename: Gunhild M
authors.initials: GM
authors.lastname: Mælandsmo
authors.affiliation: Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. Electronic address: linap@rr-research.no.
authors.forename: Lina
authors.initials: L
authors.lastname: Prasmickaite
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects; D009361:Neoplasm Invasiveness; D010641:Phenotype; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000494:pharmacology
chemical_list: D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human
keywords: Melanoma; Metabolic reprogramming; Phenotype switch; S100A4; Warburg effect