title: The metabolic interaction of cancer cells and fibroblasts - coupling between NAD(P)H and FAD, intracellular pH and hydrogen peroxide.
abstract: Alteration in the cellular energy metabolism is a principal feature of tumors. An important role in modifying cancer cell metabolism belongs to the cancer-associated fibroblasts. However, the regulation of their interaction has been poorly studied to date. In this study we monitored the metabolic status of both cell types by using the optical redox ratio and the fluorescence lifetimes of the metabolic co-factors NAD(P)H and FAD, in addition to the intracellular pH and the hydrogen peroxide levels in the cancer cells, using genetically encoded sensors. In the co-culture of human cervical carcinoma cells HeLa and human fibroblasts we observed a metabolic shift from oxidative phosphorylation toward glycolysis in cancer cells, and from glycolysis toward OXPHOS in fibroblasts, starting from Day 2 of co-culturing. The metabolic switch was accompanied by hydrogen peroxide production and slight acidification of the cytosol in the cancer cells in comparison with that of the corresponding monoculture. Therefore, our HeLa-huFb system demonstrated metabolic behavior similar to Warburg type tumors. To our knowledge, this is the first time that these 3 parameters have been investigated together in a model of tumor-stroma co-evolution. We propose that determination of the start-point of the metabolic alterations and understanding of the mechanisms of their realization can open a new ways for cancer treatment.
authors.affiliation: a Nizhny Novgorod State Medical Academy , Nizhny Novgorod , Russia.
authors.forename: Irina N
authors.initials: IN
authors.lastname: Druzhkova
authors.affiliation: a Nizhny Novgorod State Medical Academy , Nizhny Novgorod , Russia.|b Lobachevsky State University of Nizhny Novgorod , Nizhny Novgorod , Russia.
authors.forename: Marina V
authors.initials: MV
authors.lastname: Shirmanova
authors.affiliation: a Nizhny Novgorod State Medical Academy , Nizhny Novgorod , Russia.|b Lobachevsky State University of Nizhny Novgorod , Nizhny Novgorod , Russia.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Lukina
authors.affiliation: a Nizhny Novgorod State Medical Academy , Nizhny Novgorod , Russia.|b Lobachevsky State University of Nizhny Novgorod , Nizhny Novgorod , Russia.
authors.forename: Varvara V
authors.initials: VV
authors.lastname: Dudenkova
authors.affiliation: a Nizhny Novgorod State Medical Academy , Nizhny Novgorod , Russia.|c Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS , Moscow , Russia.
authors.forename: Nataliya M
authors.initials: NM
authors.lastname: Mishina
authors.affiliation: a Nizhny Novgorod State Medical Academy , Nizhny Novgorod , Russia.|b Lobachevsky State University of Nizhny Novgorod , Nizhny Novgorod , Russia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Zagaynova
mesh_terms: D002450:Cell Communication; D018920:Coculture Techniques; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism*; D005453:Fluorescence; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space; D009249:NADP / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction
chemical_list: D005182:Flavin-Adenine Dinucleotide; D009249:NADP; D006861:Hydrogen Peroxide
keywords: FLIM; NAD(P)H and FAD; Warburg effect; co-culture of cancer cells and fibroblasts; energy metabolism; genetically encoded sensors; hydrogen peroxide; intracellular pH