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Defects in cytochrome c oxidase expression induce a metabolic shift to glycolysis and carcinogenesis.

Dong DW, Srinivasan S, Guha M, Avadhani NG - Genom Data (2015)

Bottom Line: These results suggest that a defect in CcO complex initiates a retrograde signaling which can induce tumor progression.Physiological studies of these cells and esophageal tumors from human patients support these results.GEO accession number = GSE68525.

View Article: PubMed Central - PubMed

Affiliation: The Department of Biomedical Sciences, School of Veterinary Medicines, University of Pennsylvania, PA, United States ; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, PA, United States.

ABSTRACT
Mitochondrial metabolic dysfunction is often seen in cancers. This paper shows that the defect in a mitochondrial electron transport component, the cytochrome c oxidase (CcO), leads to increased glycolysis and carcinogenesis. Using whole genome microarray expression analysis we show that genetic silencing of the CcO subunit Cox4i1 in mouse C2C12 myoblasts resulted in metabolic shift to glycolysis, activated a retrograde stress signaling, and induced carcinogenesis. In the knockdown cells, the expression of Cox4i1 was less than 5% of the control and the expression of the irreversible glycolytic enzymes (Hk1, Pfkm and Pkm) increased two folds, facilitating metabolic shift to glycolysis. The expression of Ca (2+) sensitive Calcineurin (Ppp3ca) and the expression of PI3-kinase (Pik3r4 and Pik3cb) increased by two folds. This Ca (2+)/Calcineurin/PI3K retrograde stress signaling induced the up-regulation of many nuclear genes involved in tumor progression. Overall, we found 1047 genes with 2-folds expression change (with p-value less than 0.01) between the knockdown and the control, among which were 35 up-regulated genes in pathways in cancer (enrichment p-value less than 10(- 5)). Functional analysis revealed that the up-regulated genes in pathways in cancer were dominated by genes in signal transduction, regulation of transcription and PI3K signaling pathway. These results suggest that a defect in CcO complex initiates a retrograde signaling which can induce tumor progression. Physiological studies of these cells and esophageal tumors from human patients support these results. GEO accession number = GSE68525.

No MeSH data available.


Related in: MedlinePlus

Knock-down of the expression level of cytochrome c oxidase (Cox4i1 in a), and expression up-regulation of all three irreversible glycolytic enzymes Hexokinase (Hk1 in b), Phosphofructokinase (Pfkm in c) and Pyruvate Kinase (Pkm in d), as well as four other enzymes downstream of glycolysis: Acss2, Adh1, Adh7 and Aldh2 (e, f, g and h).
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f0015: Knock-down of the expression level of cytochrome c oxidase (Cox4i1 in a), and expression up-regulation of all three irreversible glycolytic enzymes Hexokinase (Hk1 in b), Phosphofructokinase (Pfkm in c) and Pyruvate Kinase (Pkm in d), as well as four other enzymes downstream of glycolysis: Acss2, Adh1, Adh7 and Aldh2 (e, f, g and h).

Mentions: The expression of Cox4i1 in the cells with Cox4i1 silenced by shRNA, referred as CcO4KD cells throughout this paper, was less than 5% of the control with scrambled shRNA (Fig. 3a). The mRNA expression levels of the irreversible glycolytic enzymes, Hexokinase (Hk1, Fig. 3b), Phosphofructokinae (Pfkm, Fig. 3c) and Pyruvate kinase (Pkm, Fig. 3d) had approximately two-folds increase. Fig. 3 also shows the mRNA expression levels of four other enzymes in the glycolytic pathway with the most fold-changes (Acss2, Adh1, Adh7 and Aldh2 in Fig. 3e to h). They were all up-regulated in CcO4KD cells and are downstream of glycolysis—important for processing pyruvate produced during glycolysis. In agreement with these data, CcO activity was reduced by about 90%, the Hk and Pfk activities increased about two folds, and glucose uptake was more than two-fold higher in CcO4KD cells [2]. These indicated that silencing Cox4i1 lead to the disruption of CcO activity and caused metabolic shift to glycolysis.


Defects in cytochrome c oxidase expression induce a metabolic shift to glycolysis and carcinogenesis.

Dong DW, Srinivasan S, Guha M, Avadhani NG - Genom Data (2015)

Knock-down of the expression level of cytochrome c oxidase (Cox4i1 in a), and expression up-regulation of all three irreversible glycolytic enzymes Hexokinase (Hk1 in b), Phosphofructokinase (Pfkm in c) and Pyruvate Kinase (Pkm in d), as well as four other enzymes downstream of glycolysis: Acss2, Adh1, Adh7 and Aldh2 (e, f, g and h).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664720&req=5

f0015: Knock-down of the expression level of cytochrome c oxidase (Cox4i1 in a), and expression up-regulation of all three irreversible glycolytic enzymes Hexokinase (Hk1 in b), Phosphofructokinase (Pfkm in c) and Pyruvate Kinase (Pkm in d), as well as four other enzymes downstream of glycolysis: Acss2, Adh1, Adh7 and Aldh2 (e, f, g and h).
Mentions: The expression of Cox4i1 in the cells with Cox4i1 silenced by shRNA, referred as CcO4KD cells throughout this paper, was less than 5% of the control with scrambled shRNA (Fig. 3a). The mRNA expression levels of the irreversible glycolytic enzymes, Hexokinase (Hk1, Fig. 3b), Phosphofructokinae (Pfkm, Fig. 3c) and Pyruvate kinase (Pkm, Fig. 3d) had approximately two-folds increase. Fig. 3 also shows the mRNA expression levels of four other enzymes in the glycolytic pathway with the most fold-changes (Acss2, Adh1, Adh7 and Aldh2 in Fig. 3e to h). They were all up-regulated in CcO4KD cells and are downstream of glycolysis—important for processing pyruvate produced during glycolysis. In agreement with these data, CcO activity was reduced by about 90%, the Hk and Pfk activities increased about two folds, and glucose uptake was more than two-fold higher in CcO4KD cells [2]. These indicated that silencing Cox4i1 lead to the disruption of CcO activity and caused metabolic shift to glycolysis.

Bottom Line: These results suggest that a defect in CcO complex initiates a retrograde signaling which can induce tumor progression.Physiological studies of these cells and esophageal tumors from human patients support these results.GEO accession number = GSE68525.

View Article: PubMed Central - PubMed

Affiliation: The Department of Biomedical Sciences, School of Veterinary Medicines, University of Pennsylvania, PA, United States ; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, PA, United States.

ABSTRACT
Mitochondrial metabolic dysfunction is often seen in cancers. This paper shows that the defect in a mitochondrial electron transport component, the cytochrome c oxidase (CcO), leads to increased glycolysis and carcinogenesis. Using whole genome microarray expression analysis we show that genetic silencing of the CcO subunit Cox4i1 in mouse C2C12 myoblasts resulted in metabolic shift to glycolysis, activated a retrograde stress signaling, and induced carcinogenesis. In the knockdown cells, the expression of Cox4i1 was less than 5% of the control and the expression of the irreversible glycolytic enzymes (Hk1, Pfkm and Pkm) increased two folds, facilitating metabolic shift to glycolysis. The expression of Ca (2+) sensitive Calcineurin (Ppp3ca) and the expression of PI3-kinase (Pik3r4 and Pik3cb) increased by two folds. This Ca (2+)/Calcineurin/PI3K retrograde stress signaling induced the up-regulation of many nuclear genes involved in tumor progression. Overall, we found 1047 genes with 2-folds expression change (with p-value less than 0.01) between the knockdown and the control, among which were 35 up-regulated genes in pathways in cancer (enrichment p-value less than 10(- 5)). Functional analysis revealed that the up-regulated genes in pathways in cancer were dominated by genes in signal transduction, regulation of transcription and PI3K signaling pathway. These results suggest that a defect in CcO complex initiates a retrograde signaling which can induce tumor progression. Physiological studies of these cells and esophageal tumors from human patients support these results. GEO accession number = GSE68525.

No MeSH data available.


Related in: MedlinePlus