Limits...
Metabolic and transcriptional profiling reveals pyruvate dehydrogenase kinase 4 as a mediator of epithelial-mesenchymal transition and drug resistance in tumor cells.

Sun Y, Daemen A, Hatzivassiliou G, Arnott D, Wilson C, Zhuang G, Gao M, Liu P, Boudreau A, Johnson L, Settleman J - Cancer Metab (2014)

Bottom Line: Such rewiring was at least partially mediated by the reduced expression of pyruvate dehydrogenase kinase 4 (PDK4), which serves as a gatekeeper of the TCA cycle by inactivating pyruvate dehydrogenase (PDH).We identified a novel interaction between PDK4 and apoptosis-inducing factor (AIF), an inner mitochondrial protein that appears to play a role in mediating this resistance.Together, these findings implicate PDK4 as a critical metabolic regulator of EMT and associated drug resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Discovery Oncology, Genentech Inc, 1 DNA Way, 94080 South San Francisco, CA USA.

ABSTRACT

Background: Accumulating preclinical and clinical evidence implicates epithelial-mesenchymal transition (EMT) in acquired resistance to anticancer drugs; however, mechanisms by which the mesenchymal state determines drug resistance remain unknown.

Results: To explore a potential role for altered cellular metabolism in EMT and associated drug resistance, we analyzed the metabolome and transcriptome of three lung cancer cell lines that were rendered drug resistant following experimental induction of EMT. This analysis revealed evidence of metabolic rewiring during EMT that diverts glucose to the TCA cycle. Such rewiring was at least partially mediated by the reduced expression of pyruvate dehydrogenase kinase 4 (PDK4), which serves as a gatekeeper of the TCA cycle by inactivating pyruvate dehydrogenase (PDH). Overexpression of PDK4 partially blocked TGFβ-induced EMT; conversely, PDK4 inhibition via RNAi-mediated knockdown was sufficient to drive EMT and promoted erlotinib resistance in EGFR mutant lung cancer cells. We identified a novel interaction between PDK4 and apoptosis-inducing factor (AIF), an inner mitochondrial protein that appears to play a role in mediating this resistance. In addition, analysis of human tumor samples revealed PDK4-low as a predictor of poor prognosis in lung cancer and that PDK4 expression is dramatically downregulated in most tumor types.

Conclusions: Together, these findings implicate PDK4 as a critical metabolic regulator of EMT and associated drug resistance.

No MeSH data available.


Related in: MedlinePlus

PDK4-low is associated with poor prognosis in human NSCLC, and PDK4 is frequently downregulated in human cancer. (A) Kaplan-Meier survival analysis of three independent lung adenocarcinoma patient cohorts shows that PDK4-low expression is associated with poor prognosis. Patients were stratified into PDK4-high (blue line, PDK4 expression above median) and PDK4-low (red line, PDK4 expression below median). Cox hazard ratios of both the individual studies and the meta-analysis of all three studies together are shown. (B)PDK4 mRNA levels in normal tissue, adenocarcinoma (ADC) and squamous cell carcinoma (SCC) of the lung. The data are from RNA-seq analysis of the TCGA NSCLC samples. Data are plotted as mean ± SEM. **p < 0.01. (C)PDK4 mRNA levels in multiple cancer types and their corresponding normal tissues from the Gene Logic database. The fold-change between the mean tumor and the mean normal tissue expression is shown in the bar plot on a log2-transformed scale. Significance was determined using a two-tailed t-test. Expression levels are shown in the boxplot on a log2-transformed scale, with display of the median expression level. The box represents 25–75 % percentile. For all indications shown in C, p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4221711&req=5

Fig5: PDK4-low is associated with poor prognosis in human NSCLC, and PDK4 is frequently downregulated in human cancer. (A) Kaplan-Meier survival analysis of three independent lung adenocarcinoma patient cohorts shows that PDK4-low expression is associated with poor prognosis. Patients were stratified into PDK4-high (blue line, PDK4 expression above median) and PDK4-low (red line, PDK4 expression below median). Cox hazard ratios of both the individual studies and the meta-analysis of all three studies together are shown. (B)PDK4 mRNA levels in normal tissue, adenocarcinoma (ADC) and squamous cell carcinoma (SCC) of the lung. The data are from RNA-seq analysis of the TCGA NSCLC samples. Data are plotted as mean ± SEM. **p < 0.01. (C)PDK4 mRNA levels in multiple cancer types and their corresponding normal tissues from the Gene Logic database. The fold-change between the mean tumor and the mean normal tissue expression is shown in the bar plot on a log2-transformed scale. Significance was determined using a two-tailed t-test. Expression levels are shown in the boxplot on a log2-transformed scale, with display of the median expression level. The box represents 25–75 % percentile. For all indications shown in C, p < 0.05.

Mentions: EMT in cancer cells is associated with increased metastasis and resistance to therapy, leading to poor clinical prognosis [2]. To determine whether PDK4 expression is associated with prognosis, we examined PDK4 mRNA expression in NSCLC clinical samples. We divided lung adenocarcinoma patient samples into PDK4-high (PDK4 expression above median) and PDK4-low (PDK4 expression below median). We did not observe any association between tumor stages and PDK4 expression levels. However, in three independent studies (GSE42127, GSE8894, and GSE3141) [29–31], we observed a significant (p = 0.01) overall association between PDK4-low tumors and poor prognosis. Thus, lung adenocarcinoma patients whose tumors have low PDK4 expression showed reduced overall survival (Figure 5A).Figure 5


Metabolic and transcriptional profiling reveals pyruvate dehydrogenase kinase 4 as a mediator of epithelial-mesenchymal transition and drug resistance in tumor cells.

Sun Y, Daemen A, Hatzivassiliou G, Arnott D, Wilson C, Zhuang G, Gao M, Liu P, Boudreau A, Johnson L, Settleman J - Cancer Metab (2014)

PDK4-low is associated with poor prognosis in human NSCLC, and PDK4 is frequently downregulated in human cancer. (A) Kaplan-Meier survival analysis of three independent lung adenocarcinoma patient cohorts shows that PDK4-low expression is associated with poor prognosis. Patients were stratified into PDK4-high (blue line, PDK4 expression above median) and PDK4-low (red line, PDK4 expression below median). Cox hazard ratios of both the individual studies and the meta-analysis of all three studies together are shown. (B)PDK4 mRNA levels in normal tissue, adenocarcinoma (ADC) and squamous cell carcinoma (SCC) of the lung. The data are from RNA-seq analysis of the TCGA NSCLC samples. Data are plotted as mean ± SEM. **p < 0.01. (C)PDK4 mRNA levels in multiple cancer types and their corresponding normal tissues from the Gene Logic database. The fold-change between the mean tumor and the mean normal tissue expression is shown in the bar plot on a log2-transformed scale. Significance was determined using a two-tailed t-test. Expression levels are shown in the boxplot on a log2-transformed scale, with display of the median expression level. The box represents 25–75 % percentile. For all indications shown in C, p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4221711&req=5

Fig5: PDK4-low is associated with poor prognosis in human NSCLC, and PDK4 is frequently downregulated in human cancer. (A) Kaplan-Meier survival analysis of three independent lung adenocarcinoma patient cohorts shows that PDK4-low expression is associated with poor prognosis. Patients were stratified into PDK4-high (blue line, PDK4 expression above median) and PDK4-low (red line, PDK4 expression below median). Cox hazard ratios of both the individual studies and the meta-analysis of all three studies together are shown. (B)PDK4 mRNA levels in normal tissue, adenocarcinoma (ADC) and squamous cell carcinoma (SCC) of the lung. The data are from RNA-seq analysis of the TCGA NSCLC samples. Data are plotted as mean ± SEM. **p < 0.01. (C)PDK4 mRNA levels in multiple cancer types and their corresponding normal tissues from the Gene Logic database. The fold-change between the mean tumor and the mean normal tissue expression is shown in the bar plot on a log2-transformed scale. Significance was determined using a two-tailed t-test. Expression levels are shown in the boxplot on a log2-transformed scale, with display of the median expression level. The box represents 25–75 % percentile. For all indications shown in C, p < 0.05.
Mentions: EMT in cancer cells is associated with increased metastasis and resistance to therapy, leading to poor clinical prognosis [2]. To determine whether PDK4 expression is associated with prognosis, we examined PDK4 mRNA expression in NSCLC clinical samples. We divided lung adenocarcinoma patient samples into PDK4-high (PDK4 expression above median) and PDK4-low (PDK4 expression below median). We did not observe any association between tumor stages and PDK4 expression levels. However, in three independent studies (GSE42127, GSE8894, and GSE3141) [29–31], we observed a significant (p = 0.01) overall association between PDK4-low tumors and poor prognosis. Thus, lung adenocarcinoma patients whose tumors have low PDK4 expression showed reduced overall survival (Figure 5A).Figure 5

Bottom Line: Such rewiring was at least partially mediated by the reduced expression of pyruvate dehydrogenase kinase 4 (PDK4), which serves as a gatekeeper of the TCA cycle by inactivating pyruvate dehydrogenase (PDH).We identified a novel interaction between PDK4 and apoptosis-inducing factor (AIF), an inner mitochondrial protein that appears to play a role in mediating this resistance.Together, these findings implicate PDK4 as a critical metabolic regulator of EMT and associated drug resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Discovery Oncology, Genentech Inc, 1 DNA Way, 94080 South San Francisco, CA USA.

ABSTRACT

Background: Accumulating preclinical and clinical evidence implicates epithelial-mesenchymal transition (EMT) in acquired resistance to anticancer drugs; however, mechanisms by which the mesenchymal state determines drug resistance remain unknown.

Results: To explore a potential role for altered cellular metabolism in EMT and associated drug resistance, we analyzed the metabolome and transcriptome of three lung cancer cell lines that were rendered drug resistant following experimental induction of EMT. This analysis revealed evidence of metabolic rewiring during EMT that diverts glucose to the TCA cycle. Such rewiring was at least partially mediated by the reduced expression of pyruvate dehydrogenase kinase 4 (PDK4), which serves as a gatekeeper of the TCA cycle by inactivating pyruvate dehydrogenase (PDH). Overexpression of PDK4 partially blocked TGFβ-induced EMT; conversely, PDK4 inhibition via RNAi-mediated knockdown was sufficient to drive EMT and promoted erlotinib resistance in EGFR mutant lung cancer cells. We identified a novel interaction between PDK4 and apoptosis-inducing factor (AIF), an inner mitochondrial protein that appears to play a role in mediating this resistance. In addition, analysis of human tumor samples revealed PDK4-low as a predictor of poor prognosis in lung cancer and that PDK4 expression is dramatically downregulated in most tumor types.

Conclusions: Together, these findings implicate PDK4 as a critical metabolic regulator of EMT and associated drug resistance.

No MeSH data available.


Related in: MedlinePlus