Limits...
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 PGC-1α (Ppargc1a in a) and its interaction partners: Crebbp in b, Pparg in c, and Rxra in d. Up-regulation of AMPK (Prkaa1 in e and Prkaa2 in f), its upstream regulator LKB1 (Stk11 in g) and a downstream gene Srebf1 in h.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4664720&req=5

f0045: Up-regulation of PGC-1α (Ppargc1a in a) and its interaction partners: Crebbp in b, Pparg in c, and Rxra in d. Up-regulation of AMPK (Prkaa1 in e and Prkaa2 in f), its upstream regulator LKB1 (Stk11 in g) and a downstream gene Srebf1 in h.

Mentions: The pathway analysis also indicated that PPAR (PGC-1α) signaling pathway was activated. PGC-1α is another regulator of mitochondrial biogenesis and function. It has been shown that PGC-1α has a positive feedback to one of its upstream regulator: Calcineurin [10]. This protein can interact with, and regulate the activities of, cAMP response element-binding protein (CREB). Fig. 9a to d shows the up-regulation of PGC-1α (Ppargc1a) and its interaction partners Crebbp, Pparg, and Rxra. Another important pathway activated was the AMP-activated protein kinase (AMPK) signaling pathway. AMPK plays an important role in insulin signaling, glucose uptake, and energy homeostasis and is involved in PGC-1α-mediated mitochondrial biogenesis. The microarray analysis indicated up-regulation of AMPK (Prkaa1 and Prkaa2 in Fig. 9e and f) and its up-stream regulator LKB1 (Stk11, Fig. 9g) as well as two downstream genes (Srebf1, Fig. 9h; and Tsc2, Fig. 6f). This is puzzling since AMPK is supposed to down-regulated Srebf1 and Tsc2 and to be a metabolic checkpoint to control cell proliferation when activated under energy stress. But it was not doing any of those in CcO4KD cells. The role of AMPK pathway in Cox4i1 knockdown needs to be studied further.


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 PGC-1α (Ppargc1a in a) and its interaction partners: Crebbp in b, Pparg in c, and Rxra in d. Up-regulation of AMPK (Prkaa1 in e and Prkaa2 in f), its upstream regulator LKB1 (Stk11 in g) and a downstream gene Srebf1 in h.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0045: Up-regulation of PGC-1α (Ppargc1a in a) and its interaction partners: Crebbp in b, Pparg in c, and Rxra in d. Up-regulation of AMPK (Prkaa1 in e and Prkaa2 in f), its upstream regulator LKB1 (Stk11 in g) and a downstream gene Srebf1 in h.
Mentions: The pathway analysis also indicated that PPAR (PGC-1α) signaling pathway was activated. PGC-1α is another regulator of mitochondrial biogenesis and function. It has been shown that PGC-1α has a positive feedback to one of its upstream regulator: Calcineurin [10]. This protein can interact with, and regulate the activities of, cAMP response element-binding protein (CREB). Fig. 9a to d shows the up-regulation of PGC-1α (Ppargc1a) and its interaction partners Crebbp, Pparg, and Rxra. Another important pathway activated was the AMP-activated protein kinase (AMPK) signaling pathway. AMPK plays an important role in insulin signaling, glucose uptake, and energy homeostasis and is involved in PGC-1α-mediated mitochondrial biogenesis. The microarray analysis indicated up-regulation of AMPK (Prkaa1 and Prkaa2 in Fig. 9e and f) and its up-stream regulator LKB1 (Stk11, Fig. 9g) as well as two downstream genes (Srebf1, Fig. 9h; and Tsc2, Fig. 6f). This is puzzling since AMPK is supposed to down-regulated Srebf1 and Tsc2 and to be a metabolic checkpoint to control cell proliferation when activated under energy stress. But it was not doing any of those in CcO4KD cells. The role of AMPK pathway in Cox4i1 knockdown needs to be studied further.

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