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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

Up-regulation of Calcineurin (Ppp3ca in a) and Calcineurin pathway: NFkB (Nfkb1 in b, Nfkb2 in c and Rela in d), NFAT (Nfatc1 in e and Nfatc3 in f), and CREB (Creb3l1 in g and Creb3l2 in h).
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f0020: Up-regulation of Calcineurin (Ppp3ca in a) and Calcineurin pathway: NFkB (Nfkb1 in b, Nfkb2 in c and Rela in d), NFAT (Nfatc1 in e and Nfatc3 in f), and CREB (Creb3l1 in g and Creb3l2 in h).

Mentions: The mitochondrial stress and the loss of mitochondrial membrane potential were indicated by the enrichment of Calcium Signaling Pathway (Table 1) and in particular by a two-fold increase in the expression level of Ca2+ sensitive Calcineurin (Ppp3ca, Fig. 4a). This signal in response to sustained elevation of [Ca2+]c had been shown to activate a set of stress responsive transcription factors: NFkB, NFAT and CREB [7]. This was consistent with the increased expression levels of Nfkb1, Nfkb2, Rela, Nfatc1, Nfatc3, Creb3l1 and Creb3l2 (Fig. 4b to h). In addition to those, this retrograde stress signaling induced increased expression of many genes involved in tumor progression. In particular, Tgfb1 and Mmp16 had 2 to 3 folds expression increase (Fig. 5a and b). In agreement with these data, Calcineurin activity increased three folds in CcO4KD cells; while for the cells further treated with BAPTA, a Ca2+ chelator, or FK506, a specific Calcineurin inhibitor, the up-regulation of Tgfb1 and Mmp16 was significantly attenuated and the glucose uptake was significantly inhibited comparing to untreated cells [2]. These indicated that the Calcineurin mediated retrograde signaling pathway played an important role in metabolic shift to glycolysis and carcinogenesis.


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)

Up-regulation of Calcineurin (Ppp3ca in a) and Calcineurin pathway: NFkB (Nfkb1 in b, Nfkb2 in c and Rela in d), NFAT (Nfatc1 in e and Nfatc3 in f), and CREB (Creb3l1 in g and Creb3l2 in h).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0020: Up-regulation of Calcineurin (Ppp3ca in a) and Calcineurin pathway: NFkB (Nfkb1 in b, Nfkb2 in c and Rela in d), NFAT (Nfatc1 in e and Nfatc3 in f), and CREB (Creb3l1 in g and Creb3l2 in h).
Mentions: The mitochondrial stress and the loss of mitochondrial membrane potential were indicated by the enrichment of Calcium Signaling Pathway (Table 1) and in particular by a two-fold increase in the expression level of Ca2+ sensitive Calcineurin (Ppp3ca, Fig. 4a). This signal in response to sustained elevation of [Ca2+]c had been shown to activate a set of stress responsive transcription factors: NFkB, NFAT and CREB [7]. This was consistent with the increased expression levels of Nfkb1, Nfkb2, Rela, Nfatc1, Nfatc3, Creb3l1 and Creb3l2 (Fig. 4b to h). In addition to those, this retrograde stress signaling induced increased expression of many genes involved in tumor progression. In particular, Tgfb1 and Mmp16 had 2 to 3 folds expression increase (Fig. 5a and b). In agreement with these data, Calcineurin activity increased three folds in CcO4KD cells; while for the cells further treated with BAPTA, a Ca2+ chelator, or FK506, a specific Calcineurin inhibitor, the up-regulation of Tgfb1 and Mmp16 was significantly attenuated and the glucose uptake was significantly inhibited comparing to untreated cells [2]. These indicated that the Calcineurin mediated retrograde signaling pathway played an important role in metabolic shift to glycolysis and carcinogenesis.

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