The expression pattern of pyruvate dehydrogenase kinases predicts prognosis and correlates with immune exhaustion in clear cell renal cell carcinoma

Renal cancer cells constitute a paradigm of tumor cells with a glycolytic reprogramming which drives metabolic alterations favouring cell survival and transformation. We studied the expression and activity of pyruvate dehydrogenase kinases (PDK1-4), key enzymes of the energy metabolism, in renal can...

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Published inScientific reports Vol. 13; no. 1; pp. 7339 - 9
Main Authors Nunes-Xavier, Caroline E., Emaldi, Maite, Mingo, Janire, Øyjord, Tove, Mælandsmo, Gunhild M., Fodstad, Øystein, Errarte, Peio, Larrinaga, Gorka, Llarena, Roberto, López, José I., Pulido, Rafael
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 05.05.2023
Nature Publishing Group
Springer Nature
Nature Portfolio
Subjects
1-Phosphatidylinositol 3-kinase
631/67/2327
631/67/589/1588
Carcinoma, Renal Cell - genetics
CD8 antigen
Cell survival
Cell viability
Clear cell-type renal cell carcinoma
Dehydrogenase
Dehydrogenases
Dichloroacetic acid
DNA microarrays
Energy metabolism
Enzymes
Gene expression
Glycolysis
Humanities and Social Sciences
Humans
Immunohistochemistry
Kidney cancer
Kidney Neoplasms - genetics
Kinases
Lymphocytes T
Medical prognosis
Metabolism
Metastases
multidisciplinary
Oxidoreductases
PDK1 protein
Phosphatidylinositol 3-Kinases
Prognosis
Protein expression
Protein Serine-Threonine Kinases - genetics
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Pyruvates
Pyruvic acid
Science
Science (multidisciplinary)
Signal transduction
Tumor cell lines
Tumor cells
Tumors
Online AccessGet full text
ISSN2045-2322
2045-2322
DOI10.1038/s41598-023-34087-x

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Abstract Renal cancer cells constitute a paradigm of tumor cells with a glycolytic reprogramming which drives metabolic alterations favouring cell survival and transformation. We studied the expression and activity of pyruvate dehydrogenase kinases (PDK1-4), key enzymes of the energy metabolism, in renal cancer cells. We analysed the expression, subcellular distribution and clinicopathological correlations of PDK1-4 by immunohistochemistry of tumor tissue microarray samples from a cohort of 96 clear cell renal cell carcinoma (ccRCC) patients. Gene expression analysis was performed on whole tumor tissue sections of a subset of ccRCC samples. PDK2 and PDK3 protein expression in tumor cells correlated with lower patient overall survival, whereas PDK1 protein expression correlated with higher patient survival. Gene expression analysis revealed molecular association of PDK2 and PDK3 expression with PI3K signalling pathway, as well as with T cell infiltration and exhausted CD8 T cells. Inhibition of PDK by dichloroacetate in human renal cancer cell lines resulted in lower cell viability, which was accompanied by an increase in pAKT. Together, our findings suggest a differential role for PDK enzymes in ccRCC progression, and highlight PDK as actionable metabolic proteins in relation with PI3K signalling and exhausted CD8 T cells in ccRCC.
AbstractList Renal cancer cells constitute a paradigm of tumor cells with a glycolytic reprogramming which drives metabolic alterations favouring cell survival and transformation. We studied the expression and activity of pyruvate dehydrogenase kinases (PDK1-4), key enzymes of the energy metabolism, in renal cancer cells. We analysed the expression, subcellular distribution and clinicopathological correlations of PDK1-4 by immunohistochemistry of tumor tissue microarray samples from a cohort of 96 clear cell renal cell carcinoma (ccRCC) patients. Gene expression analysis was performed on whole tumor tissue sections of a subset of ccRCC samples. PDK2 and PDK3 protein expression in tumor cells correlated with lower patient overall survival, whereas PDK1 protein expression correlated with higher patient survival. Gene expression analysis revealed molecular association of PDK2 and PDK3 expression with PI3K signalling pathway, as well as with T cell infiltration and exhausted CD8 T cells. Inhibition of PDK by dichloroacetate in human renal cancer cell lines resulted in lower cell viability, which was accompanied by an increase in pAKT. Together, our findings suggest a differential role for PDK enzymes in ccRCC progression, and highlight PDK as actionable metabolic proteins in relation with PI3K signalling and exhausted CD8 T cells in ccRCC.
Abstract Renal cancer cells constitute a paradigm of tumor cells with a glycolytic reprogramming which drives metabolic alterations favouring cell survival and transformation. We studied the expression and activity of pyruvate dehydrogenase kinases (PDK1-4), key enzymes of the energy metabolism, in renal cancer cells. We analysed the expression, subcellular distribution and clinicopathological correlations of PDK1-4 by immunohistochemistry of tumor tissue microarray samples from a cohort of 96 clear cell renal cell carcinoma (ccRCC) patients. Gene expression analysis was performed on whole tumor tissue sections of a subset of ccRCC samples. PDK2 and PDK3 protein expression in tumor cells correlated with lower patient overall survival, whereas PDK1 protein expression correlated with higher patient survival. Gene expression analysis revealed molecular association of PDK2 and PDK3 expression with PI3K signalling pathway, as well as with T cell infiltration and exhausted CD8 T cells. Inhibition of PDK by dichloroacetate in human renal cancer cell lines resulted in lower cell viability, which was accompanied by an increase in pAKT. Together, our findings suggest a differential role for PDK enzymes in ccRCC progression, and highlight PDK as actionable metabolic proteins in relation with PI3K signalling and exhausted CD8 T cells in ccRCC.
Renal cancer cells constitute a paradigm of tumor cells with a glycolytic reprogramming which drives metabolic alterations favouring cell survival and transformation. We studied the expression and activity of pyruvate dehydrogenase kinases (PDK1-4), key enzymes of the energy metabolism, in renal cancer cells. We analysed the expression, subcellular distribution and clinicopathological correlations of PDK1-4 by immunohistochemistry of tumor tissue microarray samples from a cohort of 96 clear cell renal cell carcinoma (ccRCC) patients. Gene expression analysis was performed on whole tumor tissue sections of a subset of ccRCC samples. PDK2 and PDK3 protein expression in tumor cells correlated with lower patient overall survival, whereas PDK1 protein expression correlated with higher patient survival. Gene expression analysis revealed molecular association of PDK2 and PDK3 expression with PI3K signalling pathway, as well as with T cell infiltration and exhausted CD8 T cells. Inhibition of PDK by dichloroacetate in human renal cancer cell lines resulted in lower cell viability, which was accompanied by an increase in pAKT. Together, our findings suggest a differential role for PDK enzymes in ccRCC progression, and highlight PDK as actionable metabolic proteins in relation with PI3K signalling and exhausted CD8 T cells in ccRCC.Renal cancer cells constitute a paradigm of tumor cells with a glycolytic reprogramming which drives metabolic alterations favouring cell survival and transformation. We studied the expression and activity of pyruvate dehydrogenase kinases (PDK1-4), key enzymes of the energy metabolism, in renal cancer cells. We analysed the expression, subcellular distribution and clinicopathological correlations of PDK1-4 by immunohistochemistry of tumor tissue microarray samples from a cohort of 96 clear cell renal cell carcinoma (ccRCC) patients. Gene expression analysis was performed on whole tumor tissue sections of a subset of ccRCC samples. PDK2 and PDK3 protein expression in tumor cells correlated with lower patient overall survival, whereas PDK1 protein expression correlated with higher patient survival. Gene expression analysis revealed molecular association of PDK2 and PDK3 expression with PI3K signalling pathway, as well as with T cell infiltration and exhausted CD8 T cells. Inhibition of PDK by dichloroacetate in human renal cancer cell lines resulted in lower cell viability, which was accompanied by an increase in pAKT. Together, our findings suggest a differential role for PDK enzymes in ccRCC progression, and highlight PDK as actionable metabolic proteins in relation with PI3K signalling and exhausted CD8 T cells in ccRCC.
ArticleNumber 7339
Author Nunes-Xavier, Caroline E.
Øyjord, Tove
López, José I.
Llarena, Roberto
Pulido, Rafael
Errarte, Peio
Emaldi, Maite
Mingo, Janire
Mælandsmo, Gunhild M.
Larrinaga, Gorka
Fodstad, Øystein
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Snippet Renal cancer cells constitute a paradigm of tumor cells with a glycolytic reprogramming which drives metabolic alterations favouring cell survival and...
Abstract Renal cancer cells constitute a paradigm of tumor cells with a glycolytic reprogramming which drives metabolic alterations favouring cell survival and...
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SubjectTerms 1-Phosphatidylinositol 3-kinase
631/67/2327
631/67/589/1588
Carcinoma, Renal Cell - genetics
CD8 antigen
Cell survival
Cell viability
Clear cell-type renal cell carcinoma
Dehydrogenase
Dehydrogenases
Dichloroacetic acid
DNA microarrays
Energy metabolism
Enzymes
Gene expression
Glycolysis
Humanities and Social Sciences
Humans
Immunohistochemistry
Kidney cancer
Kidney Neoplasms - genetics
Kinases
Lymphocytes T
Medical prognosis
Metabolism
Metastases
multidisciplinary
Oxidoreductases
PDK1 protein
Phosphatidylinositol 3-Kinases
Prognosis
Protein expression
Protein Serine-Threonine Kinases - genetics
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Pyruvates
Pyruvic acid
Science
Science (multidisciplinary)
Signal transduction
Tumor cell lines
Tumor cells
Tumors
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Title The expression pattern of pyruvate dehydrogenase kinases predicts prognosis and correlates with immune exhaustion in clear cell renal cell carcinoma
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