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The mitochondrial carrier SLC25A10 regulates cancer cell growth.

Zhou X, Paredes JA, Krishnan S, Curbo S, Karlsson A - Oncotarget (2015)

Bottom Line: The metabolic alteration was linked to an energy metabolic shift from glycolysis to mitochondrial oxidative phosphorylation illustrated by increased expression of glutamate dehydrogenase, decreased expression of lactate dehydrogenase due to down-regulation of hypoxia inducible factor 1α.We identified effects on NADPH production linked to the growth changes observed in SLC25A10 knockdown cells, demonstrated by decreased NADPH production in cells deprived of glutamine.The contribution of SLC25A10 to reprogram cell metabolism and to regulate cell growth suggests SLC25A10 as a novel target for anti-cancer strategies.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.

ABSTRACT
Dysregulation of cell metabolism is critical for the growth properties of cancer cells. The purpose of this study was to understand the role of substrate transport across the mitochondrial membrane to sustain the metabolic shift and redox defense in cancer cells. Mitochondrial carrier SLC25A10 is up-regulated in a variety of tumors and is involved in regulating intracellular levels of reactive oxygen species. We show that knockdown of SLC25A10 in A549 cells changed the growth properties to a less malignant phenotype and casued increased glutamine dependency and sensitivity to oxidative stress. The metabolic alteration was linked to an energy metabolic shift from glycolysis to mitochondrial oxidative phosphorylation illustrated by increased expression of glutamate dehydrogenase, decreased expression of lactate dehydrogenase due to down-regulation of hypoxia inducible factor 1α. We identified effects on NADPH production linked to the growth changes observed in SLC25A10 knockdown cells, demonstrated by decreased NADPH production in cells deprived of glutamine. The contribution of SLC25A10 to reprogram cell metabolism and to regulate cell growth suggests SLC25A10 as a novel target for anti-cancer strategies.

No MeSH data available.


Related in: MedlinePlus

Total intracellular NADPt, NADPH levels and NADPH/NADPt ratios in SLC25A10 knockdown A549 cells at different growth situations(A) NADPt levels in dividing, confluent and confluent cells with glutamine starvation; (B) NADPH levels in dividing, confluent and confluent cells with glutamine starvation and (C) NADPH/NADPt ratios in dividing, confluent and confluent cells with glutamine starvation. Data represented as relative change of NADPt, NADPH and NADPH/NADPt in siRNA-SLC cells compared to siRNA-CON cells. All experiments are repeated 3 times independently, all data are presented as mean ± SD. * represents p < 0.05, ** represents p < 0.01.
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Figure 3: Total intracellular NADPt, NADPH levels and NADPH/NADPt ratios in SLC25A10 knockdown A549 cells at different growth situations(A) NADPt levels in dividing, confluent and confluent cells with glutamine starvation; (B) NADPH levels in dividing, confluent and confluent cells with glutamine starvation and (C) NADPH/NADPt ratios in dividing, confluent and confluent cells with glutamine starvation. Data represented as relative change of NADPt, NADPH and NADPH/NADPt in siRNA-SLC cells compared to siRNA-CON cells. All experiments are repeated 3 times independently, all data are presented as mean ± SD. * represents p < 0.05, ** represents p < 0.01.

Mentions: To understand the mechanisms underlying the phenotype of siRNA-SLC cells, the NADPH levels were determined in dividing and confluent cells grown in complete media and in confluent cells also after 4 days of glutamine starvation. Interestingly, the total NADP increased by 20% in siRNA-SLC cells compared to siRNA-CON cells in both dividing and resting cells (Figure 3A). A slight decrease of NADPH in dividing siRNA-SLC cells and a slight increase of NADPH in resting siRNA-SLC cells (Figure 3B) resulted in a significant difference of the ratio of NADPH/total NADP in dividing cells although in resting cells the ratio between NADPH and total NADP was not altered between siRNA-SLC and siRNA-CON cells (Figure 3C). In cells grown without glutamine the difference between siRNA-SLC cells and siRNA-CON cells was pronounced. Both the amount of total NADP (Figure 3A) and NADPH (Figure 3B) were significantly decreased in the siRNA-SLC cells.


The mitochondrial carrier SLC25A10 regulates cancer cell growth.

Zhou X, Paredes JA, Krishnan S, Curbo S, Karlsson A - Oncotarget (2015)

Total intracellular NADPt, NADPH levels and NADPH/NADPt ratios in SLC25A10 knockdown A549 cells at different growth situations(A) NADPt levels in dividing, confluent and confluent cells with glutamine starvation; (B) NADPH levels in dividing, confluent and confluent cells with glutamine starvation and (C) NADPH/NADPt ratios in dividing, confluent and confluent cells with glutamine starvation. Data represented as relative change of NADPt, NADPH and NADPH/NADPt in siRNA-SLC cells compared to siRNA-CON cells. All experiments are repeated 3 times independently, all data are presented as mean ± SD. * represents p < 0.05, ** represents p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496216&req=5

Figure 3: Total intracellular NADPt, NADPH levels and NADPH/NADPt ratios in SLC25A10 knockdown A549 cells at different growth situations(A) NADPt levels in dividing, confluent and confluent cells with glutamine starvation; (B) NADPH levels in dividing, confluent and confluent cells with glutamine starvation and (C) NADPH/NADPt ratios in dividing, confluent and confluent cells with glutamine starvation. Data represented as relative change of NADPt, NADPH and NADPH/NADPt in siRNA-SLC cells compared to siRNA-CON cells. All experiments are repeated 3 times independently, all data are presented as mean ± SD. * represents p < 0.05, ** represents p < 0.01.
Mentions: To understand the mechanisms underlying the phenotype of siRNA-SLC cells, the NADPH levels were determined in dividing and confluent cells grown in complete media and in confluent cells also after 4 days of glutamine starvation. Interestingly, the total NADP increased by 20% in siRNA-SLC cells compared to siRNA-CON cells in both dividing and resting cells (Figure 3A). A slight decrease of NADPH in dividing siRNA-SLC cells and a slight increase of NADPH in resting siRNA-SLC cells (Figure 3B) resulted in a significant difference of the ratio of NADPH/total NADP in dividing cells although in resting cells the ratio between NADPH and total NADP was not altered between siRNA-SLC and siRNA-CON cells (Figure 3C). In cells grown without glutamine the difference between siRNA-SLC cells and siRNA-CON cells was pronounced. Both the amount of total NADP (Figure 3A) and NADPH (Figure 3B) were significantly decreased in the siRNA-SLC cells.

Bottom Line: The metabolic alteration was linked to an energy metabolic shift from glycolysis to mitochondrial oxidative phosphorylation illustrated by increased expression of glutamate dehydrogenase, decreased expression of lactate dehydrogenase due to down-regulation of hypoxia inducible factor 1α.We identified effects on NADPH production linked to the growth changes observed in SLC25A10 knockdown cells, demonstrated by decreased NADPH production in cells deprived of glutamine.The contribution of SLC25A10 to reprogram cell metabolism and to regulate cell growth suggests SLC25A10 as a novel target for anti-cancer strategies.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.

ABSTRACT
Dysregulation of cell metabolism is critical for the growth properties of cancer cells. The purpose of this study was to understand the role of substrate transport across the mitochondrial membrane to sustain the metabolic shift and redox defense in cancer cells. Mitochondrial carrier SLC25A10 is up-regulated in a variety of tumors and is involved in regulating intracellular levels of reactive oxygen species. We show that knockdown of SLC25A10 in A549 cells changed the growth properties to a less malignant phenotype and casued increased glutamine dependency and sensitivity to oxidative stress. The metabolic alteration was linked to an energy metabolic shift from glycolysis to mitochondrial oxidative phosphorylation illustrated by increased expression of glutamate dehydrogenase, decreased expression of lactate dehydrogenase due to down-regulation of hypoxia inducible factor 1α. We identified effects on NADPH production linked to the growth changes observed in SLC25A10 knockdown cells, demonstrated by decreased NADPH production in cells deprived of glutamine. The contribution of SLC25A10 to reprogram cell metabolism and to regulate cell growth suggests SLC25A10 as a novel target for anti-cancer strategies.

No MeSH data available.


Related in: MedlinePlus