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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 PI3-kinase (Pik3cb in a and Pik3r4 in b) and PI3-kinase pathway: Mtor in c, Hif1a in d, Ddit4 in e, Tsc2 in f, Foxo1 in g, and Prkca in h.
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f0030: Up-regulation of PI3-kinase (Pik3cb in a and Pik3r4 in b) and PI3-kinase pathway: Mtor in c, Hif1a in d, Ddit4 in e, Tsc2 in f, Foxo1 in g, and Prkca in h.

Mentions: The activation of PI3-kinase pathway was indicated by a two-fold increase in expression level of PI3-kinase—of both catalytic and regulatory subunits Pik3cb and Pik3r4 (Fig. 6a and b). It has been shown that this pathway is a major determinant of the glycolytic phenotype through Akt1 and Mtor signaling and subsequent downstream Hif1a transcription factor activation [8]. In addition to increased expression of Mtor and Hif1a (Fig. 6c and d) in CcO4KD cells, there were also increased expression levels for genes further down stream [9] of this pathway including Redd1(Ddit4), Tsc2, Foxo1 and PKCα(Prkca) (Fig. 6e to h) as well as other genes related to pathways in cancer (Fig. 5). Aerobic glycolysis supports various biosynthetic pathways and, consequently, the metabolic requirements for proliferation. Consistent with this, the CcO4KD cells developed anchorage independent growth, an important hallmark of malignant cells, and further treatment with Wortmannin, a PI3-kinase inhibitor, attenuated the glucose uptake and inhibited the colony formation of those cells [2]. These indicated that the PI3-kinase pathway played a crucial role in metabolic shift to glycolysis and in tumor progression.


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 PI3-kinase (Pik3cb in a and Pik3r4 in b) and PI3-kinase pathway: Mtor in c, Hif1a in d, Ddit4 in e, Tsc2 in f, Foxo1 in g, and Prkca in h.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0030: Up-regulation of PI3-kinase (Pik3cb in a and Pik3r4 in b) and PI3-kinase pathway: Mtor in c, Hif1a in d, Ddit4 in e, Tsc2 in f, Foxo1 in g, and Prkca in h.
Mentions: The activation of PI3-kinase pathway was indicated by a two-fold increase in expression level of PI3-kinase—of both catalytic and regulatory subunits Pik3cb and Pik3r4 (Fig. 6a and b). It has been shown that this pathway is a major determinant of the glycolytic phenotype through Akt1 and Mtor signaling and subsequent downstream Hif1a transcription factor activation [8]. In addition to increased expression of Mtor and Hif1a (Fig. 6c and d) in CcO4KD cells, there were also increased expression levels for genes further down stream [9] of this pathway including Redd1(Ddit4), Tsc2, Foxo1 and PKCα(Prkca) (Fig. 6e to h) as well as other genes related to pathways in cancer (Fig. 5). Aerobic glycolysis supports various biosynthetic pathways and, consequently, the metabolic requirements for proliferation. Consistent with this, the CcO4KD cells developed anchorage independent growth, an important hallmark of malignant cells, and further treatment with Wortmannin, a PI3-kinase inhibitor, attenuated the glucose uptake and inhibited the colony formation of those cells [2]. These indicated that the PI3-kinase pathway played a crucial role in metabolic shift to glycolysis and in tumor progression.

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