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Published on: December 26, 2016
Metabolic Suppression of a Drug-Resistant Subpopulation in Cancer Spheroid Cells
Vasilij Koshkin1, Laurie E Ailles2, Geoffrey Liu3
1Department of Chemistry and Centre for Research on Biomolecular Interactions, York University, Toronto, Ontario, Canada, M3J 1P3.
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.
Insights
Inhibiting cancer cell metabolism can fight multidrug resistance (MDR). Using 3-D models reveals that cancer cells in spheroids, unlike 2-D cultures, develop a mixed metabolic phenotype supporting MDR, especially under lactic acidosis.
Area of Science:
- Oncology
- Cancer Metabolism
- Drug Resistance
Background:
- Cancer cells exhibit distinct metabolic features, making metabolic inhibition a promising therapeutic strategy.
- Multidrug resistance (MDR) in cancer cells is often fueled by ATP, making energy production a potential target.
- Previous studies in 2-D cell cultures suggested targeting glycolysis to suppress MDR.
Purpose of the Study:
- To investigate how cellular organization, specifically 3-D spheroid models, impacts the metabolic strategies supporting multidrug resistance (MDR).
- To compare the metabolic phenotype of cancer cells in 2-D versus 3-D models concerning MDR.
- To assess the influence of tumor microenvironment conditions, like lactic acidosis, on MDR metabolism in 3-D models.
Main Methods:
- Comparison of cancer cell metabolism and MDR in 2-D monolayer cultures versus 3-D spheroid cultures.
- Analysis of metabolic phenotypes, including glycolysis and oxidative phosphorylation, in different cellular models.
- Evaluation of MDR support under conditions mimicking the solid tumor microenvironment, such as lactic acidosis.
Main Results:
- Transitioning from 2-D to 3-D spheroid models revealed a distinct subpopulation of cancer cells with enhanced MDR transport capacity.
- This 3-D subpopulation exhibited a mixed glycolytic and oxidative metabolic phenotype for MDR support, differing from 2-D cultures.
- Spheroids grown under lactic acidosis conditions showed a further shift towards an oxidative metabolic phenotype, enhancing MDR.
Conclusions:
- The 3-D cellular organization fundamentally alters the metabolic approach to supporting multidrug resistance (MDR) in cancer cells.
- The findings challenge the direct applicability of 2-D model-based strategies for targeting MDR metabolism in a clinical context.
- Understanding 3-D-specific metabolic adaptations, especially under tumor-like conditions, is crucial for developing effective MDR-targeting cancer therapies.
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