The Warburg effect, a phenomenon discovered by Otto Warburg in 1924, reflects a shift to an inefficient metabolism in cancer cells, in which an increase in the inefficient production of ATP via glycolysis leads to the secretion of lactate, even in the presence of oxygen (termed aerobic glycolysis) The underlying biochemical and molecular mechanism of the Warburg’s effect remain unclear, but it is likely a combination of mitochondrial malfunction (Wallace 2005) oncogenic alteration (Dang, Semenza 1999), as well as adaptive responses to the tumour microenvironment. We questioned the relevance of “metabolic reprogramming” in cisplatin-resistance, by studying mitochondrial function and metabolism in human ovary carcinoma cisplatin-resistant (C13) and -sensitive (2008) cell lines. C13 cells, in comparison 2008 cells, showed lower basal oxygen consumption (4.2±0.2 vs 6.5±0.7 fmol/cell/min, P<0.005) and lower basal transmembrane mitochondrial potential (ΔΨm) (18.7±1.5 vs 32.2±1 MFI P<0.001). Also C13 cells showed lower sensitivity to rotenone and oligomycin mitochondrial inhibitors. To further investigate the impact of mitochondria in the cisplatin- resistance, 2008 and C13 cells were depleted of their mitochondrial DNA (rho0-clones). Notably, the cytotoxicity of cisplatin was lower in 2008-rho0clones than in 2008 cells (IC50 3.56 µM and 0.72 µM) but similar between C13-rho0 and C13 cells (5.49 µM and 6.49 µM ). Next, the time-course of cell viability in glucose free-galactose medium, indicated that C13 cells were more strictly dependent on glucose, than 2008 cells. 1H-NMR spectroscopy evidenced higher basal content of intracellular GSH and mobile lipids (MLs) in C13 cells, as compared to 2008 cells, and Nile red staining confirmed the higher lipid accumulation, mainly within cytoplasmic droplets, in C13 cells. The findings allow to argue a “metabolic remodelling” of ovary carcinoma cells to a lipogenic phenotype, including alteration of mitochondrial function, as an advantageous mechanism to escape cisplatin-induced apoptosis. Investigation on how this metabolic change is achieved and how it influences resistance to platinum drugs in other neoplasms will be of relevance in chemotherapy and should be further evaluated to improve the clinical impact of platinum drugs. Dang, Semenza. (1999). Trends Biochem Sci. 24:68-72. Wallace. (2005) Annu Rev Genet. 39:359-407.

Mithocondria defect and cisplatin resistance: relationships on ovarian cancer cells.

MONTOPOLI, MONICA;BELLANDA, MASSIMO;RAGAZZI, EUGENIO;CATANZARO, DANIELA;FROLDI, GUGLIELMINA;MAMMI, STEFANO;CAPARROTTA, LAURA
2011

Abstract

The Warburg effect, a phenomenon discovered by Otto Warburg in 1924, reflects a shift to an inefficient metabolism in cancer cells, in which an increase in the inefficient production of ATP via glycolysis leads to the secretion of lactate, even in the presence of oxygen (termed aerobic glycolysis) The underlying biochemical and molecular mechanism of the Warburg’s effect remain unclear, but it is likely a combination of mitochondrial malfunction (Wallace 2005) oncogenic alteration (Dang, Semenza 1999), as well as adaptive responses to the tumour microenvironment. We questioned the relevance of “metabolic reprogramming” in cisplatin-resistance, by studying mitochondrial function and metabolism in human ovary carcinoma cisplatin-resistant (C13) and -sensitive (2008) cell lines. C13 cells, in comparison 2008 cells, showed lower basal oxygen consumption (4.2±0.2 vs 6.5±0.7 fmol/cell/min, P<0.005) and lower basal transmembrane mitochondrial potential (ΔΨm) (18.7±1.5 vs 32.2±1 MFI P<0.001). Also C13 cells showed lower sensitivity to rotenone and oligomycin mitochondrial inhibitors. To further investigate the impact of mitochondria in the cisplatin- resistance, 2008 and C13 cells were depleted of their mitochondrial DNA (rho0-clones). Notably, the cytotoxicity of cisplatin was lower in 2008-rho0clones than in 2008 cells (IC50 3.56 µM and 0.72 µM) but similar between C13-rho0 and C13 cells (5.49 µM and 6.49 µM ). Next, the time-course of cell viability in glucose free-galactose medium, indicated that C13 cells were more strictly dependent on glucose, than 2008 cells. 1H-NMR spectroscopy evidenced higher basal content of intracellular GSH and mobile lipids (MLs) in C13 cells, as compared to 2008 cells, and Nile red staining confirmed the higher lipid accumulation, mainly within cytoplasmic droplets, in C13 cells. The findings allow to argue a “metabolic remodelling” of ovary carcinoma cells to a lipogenic phenotype, including alteration of mitochondrial function, as an advantageous mechanism to escape cisplatin-induced apoptosis. Investigation on how this metabolic change is achieved and how it influences resistance to platinum drugs in other neoplasms will be of relevance in chemotherapy and should be further evaluated to improve the clinical impact of platinum drugs. Dang, Semenza. (1999). Trends Biochem Sci. 24:68-72. Wallace. (2005) Annu Rev Genet. 39:359-407.
35° Congresso SIF: Il farmaco dalla ricerca alla salute dell'uomo.
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