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Defects in Cytochrome C Oxidase Expression Induce a Metabolic Shift to Glycolysis and Carcinogenesis

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Defects in Cytochrome C Oxidase Expression Induce a Metabolic Shift to Glycolysis and Carcinogenesis Genomics Data 6 (2015) 99–107 Contents lists available at ScienceDirect Genomics Data journal homepage: http://www.journals.elsevier.com/genomics-data/ Data in Brief Defects in cytochrome c oxidase expression induce a metabolic shift to glycolysis and carcinogenesis Dawei W. Dong a,b,⁎, Satish Srinivasan a,MantiGuhaa, Narayan G. Avadhani a a The Department of Biomedical Sciences, School of Veterinary Medicines, University of Pennsylvania, PA, United States b Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, PA, United States article info abstract Article history: Mitochondrial metabolic dysfunction is often seen in cancers. This paper shows that the defect in a mitochondrial Received 29 June 2015 electron transport component, the cytochrome c oxidase (CcO), leads to increased glycolysis and carcinogenesis. Received in revised form 19 July 2015 Using whole genome microarray expression analysis we show that genetic silencing of the CcO subunit Cox4i1 in Accepted 26 July 2015 mouse C2C12 myoblasts resulted in metabolic shift to glycolysis, activated a retrograde stress signaling, and in- Available online 14 August 2015 duced carcinogenesis. In the knockdown cells, the expression of Cox4i1 was less than 5% of the control and the Keywords: expression of the irreversible glycolytic enzymes (Hk1, Pfkm and Pkm) increased two folds, facilitating metabolic 2+ Genome expression shift to glycolysis. The expression of Ca sensitive Calcineurin (Ppp3ca) and the expression of PI3-kinase (Pik3r4 2+ Functional analysis and Pik3cb) increased by two folds. This Ca /Calcineurin/PI3K retrograde stress signaling induced the up- Tumor progression regulation of many nuclear genes involved in tumor progression. Overall, we found 1047 genes with 2-folds ex- Mitochondrial metabolic dysfunction pression change (with p-value less than 0.01) between the knockdown and the control, among which were 35 Cytochrome c oxidase defects 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 retro- grade signaling which can induce tumor progression. Physiological studies of these cells and esophageal tumors from human patients support these results. GEO accession number = GSE68525. © 2015 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Specifications 2. Direct link to deposited source codes Organism/cell line/tissue Mus musculus/C2C12 myoblasts http://code.vet.upenn.edu/download/CcOdefect/ Sequencer or array type Affymetrix GeneChip Mouse Gene 2.0ST Arrays scanned by Affymetrix GeneChip Scanner 3000 Data format Raw CEL files and RMA summary 3. Experimental Design, Materials and Methods Experimental factors Tumorigenic vs. control cells Experimental features Genetic silencing of Cox4i1 by shRNA induced a 3.1. Sample preparation tumorigenic phenotype in C2C12 myoblasts, the mRNA expression of which was compared to the control with scrambled shRNA Cells were grown in Dulbecco's Modified Eagle medium supple- mented with 10% fetal bovine serum and 0.1% penicillin/streptomycin. In case of Cox4i1 silenced (C4KD) cells, the medium was further supple- mented with 1 mM Pyruvate and 50 μg/ml Uridine. RNA was prepared using Qiagen Rneasy kit following manufacturer's instructions. 5.5 μg single-stranded cDNA was fragmented and labeled using the Affymetrix 1. Direct link to deposited data GeneChip WT Terminal Labeling kit (PN: 900671). Labeled cDNA (3.25 μg) was hybridized for 17 h at 45°C to Affymetrix GeneChip http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE68525 Mouse Gene 2.0ST Arrays (PN: 902118). 3.2. Microarray analysis ⁎ Corresponding author at: The Department of Biomedical Sciences, School of Veterinary Medicines, University of Pennsylvania, PA, United States. The data were processed by Affymetrix Expression Console using E-mail address: [email protected] (D.W. Dong). Probeset-Summarize-Engine with default setting of the robust multi- http://dx.doi.org/10.1016/j.gdata.2015.07.031 2213-5960/© 2015 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 100 D.W. Dong et al. / Genomics Data 6 (2015) 99–107 array average (RMA, [1]) method to calculate the expression level for 3.3. Statistical analysis each probeset of the array (in log2 unit, online file: rma-gene- full.summary.txt). For quality control, we performed principal Fold changes are presented as the mean ± s.e.m. (standard error of component analysis (PCA) based on RMA expression levels of the sam- the mean) and p-values were determined by one-tailed Welch's t-test, ples. The projection to the most dominant two components is shown in which is used to test the hypothesis that two populations have equal Fig. 1a. The control samples formed a single cluster separable from the means and is more reliable than Student's t-test when the samples knockdown. However, the knockdown samples are further branched from two populations have unequal variances and unequal sample into two groups. The grouping is also clearly shown (Fig. 1b) by the cor- sizes [3]. So for a statistic t and a degrees of freedom v,thep-value is cal- relation coefficient value (with each probe mean over all samples re- culated by moved) between two samples: if the two samples come from the same group, the value is high (above 0.6); if they come from different 1 v 1 groups, the value is low or negative. Further investigation of the biolog- I v ; ð1Þ þ 2 ical samples showed that C4KD1 and C4KD2 cells contained nearly 90% 2 v t 2 2 reduced Cox4i1 mRNA and protein as compared to control cells [2], while in C4KD3 cells the reduction was not as much (probably due to where I is the regularized incomplete beta function. The statistic t is de- a less effective population selection by antibiotic resulting a mixture fined by the following formula: of knockdown and non-knockdown cells). This is consistent with microarray results: for both C4KD1 and C4KD2 the reduction were − ~20 folds, for C4KD3 only ~2 folds. In the following analysis, C4KD3 ¼ pmffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi1 m2 ð Þ t þ 2 was excluded. s1 s2 Fig. 1. Quality control for data analysis. The array expression data (from all 41,345 probes) of each sample are projected to the first two components of PCA, P1 and P2 in a, showing the separation of 6 samples into three groups. This separation is also shown in the 6×6 matrix of the correlation coefficients between samples (b). The plot in (c) shows the selection criteria for significant fold change in individual gene expression: the absolute fold change has to be bigger than 20.5 (red and blue dots), and the p-value has to be smaller than 0.05. For functional analysis, the selected genes are ranked by p-value and are further selected by Benjamini-Hocheberg method to limit FDR (d). D.W. Dong et al. / Genomics Data 6 (2015) 99–107 101 where m1 and s1 are the mean and the s.e.m of the 1st sample, and m2 and Table 1 Top 64 most enriched pathways in the C4KD cells compared to the control cells. s2 of the 2nd sample. The degrees of freedom v is approximated by The top pathways were selected with the number of hits ≥ 20 and the p-value b 0.15. ÀÁ 2 s2 þ s2 Hits Size % p-value Kegg id Name of pathway v ≈ 1 2 ð3Þ s4 s4 330 1271 26 1.3e-11 01100 Metabolic pathways 1 þ 2 127 397 32 6.4e-11 05200 Pathways in cancer v1−1 v2−1 95 352 27 5.3-e05 04151 PI3K-Akt signaling pathway 74 232 32 6.3e-07 05203 Viral carcinogenesis where v1 and v2 are the 1st and 2nd sample size, respectively. All calcu- 73 206 35 6.1e-09 05205 Proteoglycans in cancer lations are performed using RMA expression levels, i.e., in log2 unit. For a 71 276 26 1.8e-03 05206 MicroRNAs in cancer given gene, a fold change N20.5 with a p-value b0.05 was considered sta- 68 254 27 7.2e-04 04010 MAPK signaling pathway tistically significant. Fig. 1b shows the distribution of fold change versus 66 208 32 3.0e-06 04510 Focal adhesion 64 170 38 3.4e-09 03013 RNA transport p-value for the full probeset of the Affymetrix GeneChip Mouse Gene 64 218 29 6.3e-05 01130 Biosynthesis of antibiotics 2.0ST Arrays. Out of 41,345 probes, 6049 had statistically significant 64 235 27 6.3e-04 04144 Endocytosis fold change (red dots in Fig. 1c). Among those are 4908 uniquely iden- 60 145 41 1.1e-10 03010 Ribosome tified genes (out of 26,515 Entrez genes of the array). Each individual 58 230 25 6.9e-03 04014 Ras signaling pathway gene expression presented in the paper is among those. 54 214 25 8.7e-03 04015 Rap1 signaling pathway 50 133 38 1.8e-07 03040 Spliceosome 49 118 42 5.5e-09 04919 Thyroid hormone signaling pathway 3.4. Pathway analysis 48 177 27 3.0e-03 05202 Transcriptional misregulation in cancer 45 168 27 5.1e-03 04141 Protein processing in endoplasmic reticulum The list of genes with significant fold change was uploaded to KEGG 45 172 26 8.1e-03 04022 cGMP-PKG signaling pathway 45 179 25 1.7e-02 00230 Purine metabolism Mapper to search pathways (http://www.genome.jp/kegg/tool/map_ 44 198 22 1.1e-01 04062 Chemokine signaling pathway pathway1.html, [4]).
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  • Glucokinase Intrinsically Regulates Glucose Sensing and Glucagon
    www.nature.com/scientificreports OPEN Glucokinase intrinsically regulates glucose sensing and glucagon secretion in pancreatic alpha cells Tilo Moede1*, Barbara Leibiger1, Pilar Vaca Sanchez1, Elisabetta Daré1, Martin Köhler1, Thusitha P. Muhandiramlage1, Ingo B. Leibiger1,2 & Per‑Olof Berggren1,2 The secretion of glucagon by pancreatic alpha cells is regulated by a number of external and intrinsic factors. While the electrophysiological processes linking a lowering of glucose concentrations to an increased glucagon release are well characterized, the evidence for the identity and function of the glucose sensor is still incomplete. In the present study we aimed to address two unsolved problems: (1) do individual alpha cells have the intrinsic capability to regulate glucagon secretion by glucose, and (2) is glucokinase the alpha cell glucose sensor in this scenario. Single cell RT‑PCR was used to confrm that glucokinase is the main glucose‑phosphorylating enzyme expressed in rat pancreatic alpha cells. Modulation of glucokinase activity by pharmacological activators and inhibitors led to a lowering or an increase of the glucose threshold of glucagon release from single alpha cells, measured by TIRF microscopy, respectively. Knockdown of glucokinase expression resulted in a loss of glucose control of glucagon secretion. Taken together this study provides evidence for a crucial role of glucokinase in intrinsic glucose regulation of glucagon release in rat alpha cells. Secretion of the blood glucose elevating hormone glucagon by pancreatic alpha cells increases rapidly when blood glucose concentration drops. An increase in glucagon leads to stimulation of glucose production by the liver and thereby an increase in blood glucose levels 1,2.
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