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. 2013 Apr 10;8(4):e61035.
doi: 10.1371/journal.pone.0061035. Print 2013.

Prognostic relevance of cytochrome C oxidase in primary glioblastoma multiforme

Corinne E Griguer  1 , Alan B Cantor, Hassan M Fathallah-Shaykh, G Yancey Gillespie, Amber S Gordon, James M Markert, Ivan Radovanovic, Virginie Clement-Schatlo, Chevis N Shannon, Claudia R Oliva
Affiliations

Prognostic relevance of cytochrome C oxidase in primary glioblastoma multiforme

Corinne E Griguer et al. PLoS One. .

Abstract

Patients with primary glioblastoma multiforme (GBM) have one of the lowest overall survival rates among cancer patients, and reliable biomarkers are necessary to predict patient outcome. Cytochrome c oxidase (CcO) promotes the switch from glycolytic to OXPHOS metabolism, and increased CcO activity in tumors has been associated with tumor progression after chemotherapy failure. Thus, we investigated the relationship between tumor CcO activity and the survival of patients diagnosed with primary GBM. A total of 84 patients with grade IV glioma were evaluated in this retrospective cohort study. Cumulative survival was calculated by the Kaplan-Meier method and analyzed by the log-rank test, and univariate and multivariate analyses were performed with the Cox regression model. Mitochondrial CcO activity was determined by spectrophotometrically measuring the oxidation of cytochrome c. High CcO activity was detected in a subset of glioma tumors (∼30%), and was an independent prognostic factor for shorter progression-free survival and overall survival [P = 0.0087 by the log-rank test, hazard ratio = 3.57 for progression-free survival; P<0.001 by the log-rank test, hazard ratio = 10.75 for overall survival]. The median survival time for patients with low tumor CcO activity was 14.3 months, compared with 6.3 months for patients with high tumor CcO activity. High CcO activity occurs in a significant subset of high-grade glioma patients and is an independent predictor of poor outcome. Thus, CcO activity may serve as a useful molecular marker for the categorization and targeted therapy of GBMs.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Determination of CcO Activity Levels.
Panel A shows the representative time course curves of CcO activity (top) and CS activity (bottom). CcO activity was determined by spectrophotometrically measuring the oxidation of cytochrome c, as indicated by the decrease of absorbance at 550 nm. CS activity was determined by measuring spectrophotometric thionitrobenzoic acid (TNB) production, as indicated by the increase of absorbance at 412 nm. For each tissue sample, activities were measured at least twice at protein concentrations that ensured the linearity of the reaction. CcO-specific and CS-specific activities were calculated using the slopes of the curves, and activities were expressed as nanomoles of cytochrome c oxidized per minute per milligram of protein. Red and black lines denote duplicate determinations of a representative tissue. Panel B shows representative CcO/CS ratios from normal brain (epilepsy patients, gray bars) and from primary glioma tissue samples (red bars). Bars represent the average of at least two independent determinations ± SEM.
Figure 2
Figure 2. Kaplan–Meier Estimates of Overall Survival and Progression Free Survival.
Panel A shows the probability of overall survival and Panel B shows the probability of progression-free survival for the 58 patients with grade IV primary glioblastoma in the training set. Panel C shows the difference in the probability of overall survival for patients with high and low tumor CcO activity (P<0.0001 by the log-rank test; hazard ratio for death in patients with high tumor CcO activity, 10.75; 95% CI, 3.79 to 30.51). Panel D shows the difference in the probability of progression-free survival for patients with high and low tumor CcO activity (P = 0.0087 by the log-rank test; hazard ratio for death in patients with high tumor CcO activity, 3.57; 95% CI, 1.38 to 9.22). Black circles denote censored points, and the numbers between brackets indicate the median survival for each group. CcO denotes cytochrome c oxidase.
Figure 3
Figure 3. Kaplan–Meier Estimates of Overall Survival and Progression Free Survival in an Independent Validation Set.
A total of 27 primary glioma tissue samples from the University of Geneva, Switzerland, were analyzed in the validation set. Panel A shows the probability of overall survival and Panel B shows the probability of progression-free survival for these patients. Panel C shows the difference in the probability of overall survival for patients with high and low tumor CcO activity (a P<0.0001 by the log-rank test; hazard ratio for death in patients with high tumor CcO activity, 17; 95% CI, 16.69 to 18.07). Panel D shows the difference in the probability of progression-free survival for patients with high and low tumor CcO activity (hazard ratio for death in patients with high CcO activity, 5.31; 95% CI, 1.2 to 23.58). Black circles denote censored points, and the numbers between brackets indicate the median survival for each group. CcO denotes cytochrome c oxidase.
Figure 4
Figure 4. Multivariate Analysis of Survival for the Cohorts with High and Low CcO Activity.
Panel A shows the Kaplan-Meier estimate of the probability of overall survival, according to CcO activity, in all 84 patients combined from the training and validation tissue cohorts (P<0.0001 by the log-rank test; hazard ratio for death in patients with high CcO activity, 24.20; 95% CI, 9.12 to 34.20). Red denotes tumors with low CcO activity and blue denotes tumors with high CcO activity. Panel B, C, D, and E show the probability of survival in patients with high (left) and low (right) CcO activity with respect to age (Panel B; hazard ratio, 0.24; P = 0.14), gender (Panel C; hazard ratio, 0.58; P = 0.42), treatment administered (Panel D; hazard ratio, 0.39; P = 0.05) and MGMT promoter methylation status (Panel E; hazard ratio, 0.9; P = 0.83). Black circles denote censored points, and the numbers between brackets indicate the median survival for each group. CcO denotes cytochrome c oxidase, F denotes female, M denotes male, TMZ denotes temozolomide, and Rad denotes radiotherapy.
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