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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

Functional groups of significantly regulated genes of CcO4KD cells: a, the number of genes with significant fold-changes in different functional groups; b, the Venn diagrams of up-regulated genes in signal transduction (pink), regulation of transcription (green) and pathways in cancer (brown); c, the Venn diagrams of up-regulated genes in signal transduction (pink), PI3K pathway (green) and pathways in cancer (brown).
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f0035: Functional groups of significantly regulated genes of CcO4KD cells: a, the number of genes with significant fold-changes in different functional groups; b, the Venn diagrams of up-regulated genes in signal transduction (pink), regulation of transcription (green) and pathways in cancer (brown); c, the Venn diagrams of up-regulated genes in signal transduction (pink), PI3K pathway (green) and pathways in cancer (brown).

Mentions: Bmp4, Arnt2, Tgfb2, Col4a5 and Ar (shown in Fig. 5c to g) were the five most up-regulated genes in Pathways in Cancer. Ccne1 (shown in Fig. 5h) was the most down-regulated gene in Pathways in Cancer. Col4a5 and Ccne1 are in PI3K-Akt Pathway and their corresponding up and down regulation are consistent with their role in cancers. Furthermore, Ar, Bmp4 and Tgfb2 are involved in signal transduction and Ar, Arnt2 and Bmp4 are involved in regulation of transcription. To gain additional understanding of functional roles of the most significantly regulated genes of CcO4KD cells, we further narrowed down the list of genes and did functional annotation of the list. There were 1047 genes with 2-fold or more expression change and p-value less than 0.01. The distribution of those genes in the three dominate pathways and 10 different functional groups is shown in Fig. 7a. Among those were 38 significantly regulated genes in Pathways in Cancer (enrichment p-value less than 10− 6). Table 2 shows the fold changes and the p-values of the 38 genes. 35 genes in Pathways in Cancer were up-regulated (enrichment p-value less than 10− 5). 24, 15 and 11 of these up-regulated genes in pathways in cancer are in functional groups of signal transduction, regulation of transcription and PI3K pathway, respectively. There were extensive overlaps (11) between those in signal transduction and regulation of transcription (Fig. 7b). There were also overlaps (5) between those in signal transduction and PI3K pathway (Fig. 7c). There was only one (Rxra) overlap between those in regulation of transcription and PI3K pathway. Only two genes (Dapk2 and Ncoa4) in pathways in cancer were not in any of the other three functional groups. Interestingly, none of genes in pathways in cancer was in metabolic pathway. It appears that CcO defects induced Calcineurin/PI3K retrograde signaling which in turns induced up-regulation of genes involved in signal transduction and regulation of transcription, up-regulation of genes related to pathways in cancer, 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)

Functional groups of significantly regulated genes of CcO4KD cells: a, the number of genes with significant fold-changes in different functional groups; b, the Venn diagrams of up-regulated genes in signal transduction (pink), regulation of transcription (green) and pathways in cancer (brown); c, the Venn diagrams of up-regulated genes in signal transduction (pink), PI3K pathway (green) and pathways in cancer (brown).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0035: Functional groups of significantly regulated genes of CcO4KD cells: a, the number of genes with significant fold-changes in different functional groups; b, the Venn diagrams of up-regulated genes in signal transduction (pink), regulation of transcription (green) and pathways in cancer (brown); c, the Venn diagrams of up-regulated genes in signal transduction (pink), PI3K pathway (green) and pathways in cancer (brown).
Mentions: Bmp4, Arnt2, Tgfb2, Col4a5 and Ar (shown in Fig. 5c to g) were the five most up-regulated genes in Pathways in Cancer. Ccne1 (shown in Fig. 5h) was the most down-regulated gene in Pathways in Cancer. Col4a5 and Ccne1 are in PI3K-Akt Pathway and their corresponding up and down regulation are consistent with their role in cancers. Furthermore, Ar, Bmp4 and Tgfb2 are involved in signal transduction and Ar, Arnt2 and Bmp4 are involved in regulation of transcription. To gain additional understanding of functional roles of the most significantly regulated genes of CcO4KD cells, we further narrowed down the list of genes and did functional annotation of the list. There were 1047 genes with 2-fold or more expression change and p-value less than 0.01. The distribution of those genes in the three dominate pathways and 10 different functional groups is shown in Fig. 7a. Among those were 38 significantly regulated genes in Pathways in Cancer (enrichment p-value less than 10− 6). Table 2 shows the fold changes and the p-values of the 38 genes. 35 genes in Pathways in Cancer were up-regulated (enrichment p-value less than 10− 5). 24, 15 and 11 of these up-regulated genes in pathways in cancer are in functional groups of signal transduction, regulation of transcription and PI3K pathway, respectively. There were extensive overlaps (11) between those in signal transduction and regulation of transcription (Fig. 7b). There were also overlaps (5) between those in signal transduction and PI3K pathway (Fig. 7c). There was only one (Rxra) overlap between those in regulation of transcription and PI3K pathway. Only two genes (Dapk2 and Ncoa4) in pathways in cancer were not in any of the other three functional groups. Interestingly, none of genes in pathways in cancer was in metabolic pathway. It appears that CcO defects induced Calcineurin/PI3K retrograde signaling which in turns induced up-regulation of genes involved in signal transduction and regulation of transcription, up-regulation of genes related to pathways in cancer, 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