title: Metabolic Suppression of a Drug-Resistant Subpopulation in Cancer Spheroid Cells.
abstract: Inhibition of metabolic features which distinguish cancer cells from their non-malignant counterparts is a promising approach to cancer treatment. Energy support for drug extrusion in multidrug resistance (MDR) is a potential target for metabolic inhibition. Two major sources of ATP-based metabolic energy are partial (glycolysis) and complete (mitochondrial oxidative phosphorylation) oxidation of metabolic fuels. In cancer cells, the balance between them tends to be shifted toward glycolysis; this shift is considered to be characteristic of the cancer metabolic phenotype. Numerous earlier studies, conducted with cells cultured in a monolayer (2-D model), suggested inhibition of glycolytic ATP production as an efficient tool to suppress MDR in cancer cells. Yet, more recent work challenged the appropriateness of the 2-D model for such studies and suggested that a more clinically relevant approach would utilize a more advanced cellular model such as a 3-D model. Here, we show that the transition from the 2-D model (cultured monolayer) to a 3-D model (cultured spheroids) introduces essential changes into the concept of energetic suppression of MDR. The 3-D cell organization leads to the formation of a discrete cell subpopulation (not formed in the 2-D model) with elevated MDR transport capacity. This subpopulation has a specific metabolic phenotype (mixed glycolytic/oxidative MDR support) different from that of cells cultured in the 2-D model. Finally, the shift to the oxidative phenotype becomes greater when the spheroids are grown under conditions of lactic acidosis that are typical for solid tumors. The potential clinical significance of these findings is discussed.
authors.affiliation: Department of Chemistry and Centre for Research on Biomolecular Interactions, York University, Toronto, Ontario, Canada, M3J 1P3.
authors.forename: Vasilij
authors.initials: V
authors.lastname: Koshkin
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada, N5G 1L7.
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Ailles
authors.affiliation: Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Hospital, Toronto, Ontario, Canada, M5G 2C4.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Centre for Research on Biomolecular Interactions, York University, Toronto, Ontario, Canada, M3J 1P3.
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Krylov
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D061986:MCF-7 Cells; D008954:Models, Biological; D018874:Spheroids, Cellular / Q000166:cytology* / Q000378:metabolism*
chemical_list: D000255:Adenosine Triphosphate
keywords: BIOENERGETICS; CANCER METABOLIC SUBTYPES; CELL SPHEROIDS; LACTIC ACIDOSIS; MULTIDRUG RESISTANCE