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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

Three major pathways of significantly regulated genes of CcO4KD cells—Metabolic Pathways, Pathways in Cancer and PI3K-Akt Signaling Pathway: a, overlaps between the three; b, Metabolic Pathways' overlaps with others; c, Pathways in Cancer's overlaps with others; d, PI3K-Akt Signaling Pathway's overlaps with others.
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f0010: Three major pathways of significantly regulated genes of CcO4KD cells—Metabolic Pathways, Pathways in Cancer and PI3K-Akt Signaling Pathway: a, overlaps between the three; b, Metabolic Pathways' overlaps with others; c, Pathways in Cancer's overlaps with others; d, PI3K-Akt Signaling Pathway's overlaps with others.

Mentions: Metabolic Pathways, Pathways in Cancer and PI3K-Akt Signaling Pathway were the top three pathways enriched with the genes of significant expression change due to the CcO complex defect (Table 1). Among the three, Pathways in Cancer and PI3K-Akt Signaling Pathway had a lots of overlaps while they had little overlaps with Metabolic Pathways (Fig. 2a). The 330 genes enriching Metabolic Pathways were distributed in different pathways of metabolism (Fig. 2b). Oxidative Phosphorylation was the leading one. Another enriched one was Glycolysis/Gluconeogenesis. Glycolysis is known to be responsible for energy generation if Oxidative Phosphorylation is interrupted. The 127 genes enriching Pathways in Cancer were sub-divided into many pathways (Fig. 2c). Interestingly, genes in PI3K-Akt Signaling Pathway accounted for one third overall and contributed about half to others except Wnt and Hippo signaling pathways.


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)

Three major pathways of significantly regulated genes of CcO4KD cells—Metabolic Pathways, Pathways in Cancer and PI3K-Akt Signaling Pathway: a, overlaps between the three; b, Metabolic Pathways' overlaps with others; c, Pathways in Cancer's overlaps with others; d, PI3K-Akt Signaling Pathway's overlaps with others.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0010: Three major pathways of significantly regulated genes of CcO4KD cells—Metabolic Pathways, Pathways in Cancer and PI3K-Akt Signaling Pathway: a, overlaps between the three; b, Metabolic Pathways' overlaps with others; c, Pathways in Cancer's overlaps with others; d, PI3K-Akt Signaling Pathway's overlaps with others.
Mentions: Metabolic Pathways, Pathways in Cancer and PI3K-Akt Signaling Pathway were the top three pathways enriched with the genes of significant expression change due to the CcO complex defect (Table 1). Among the three, Pathways in Cancer and PI3K-Akt Signaling Pathway had a lots of overlaps while they had little overlaps with Metabolic Pathways (Fig. 2a). The 330 genes enriching Metabolic Pathways were distributed in different pathways of metabolism (Fig. 2b). Oxidative Phosphorylation was the leading one. Another enriched one was Glycolysis/Gluconeogenesis. Glycolysis is known to be responsible for energy generation if Oxidative Phosphorylation is interrupted. The 127 genes enriching Pathways in Cancer were sub-divided into many pathways (Fig. 2c). Interestingly, genes in PI3K-Akt Signaling Pathway accounted for one third overall and contributed about half to others except Wnt and Hippo signaling pathways.

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