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Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts

Pyruvate dehydrogenase kinase 1 (PDK1) blockade triggers are well characterized in vitro metabolic alterations in cancer cells, including reduced glycolysis and increased glucose oxidation. Here, by gene expression profiling and digital pathology-mediated quantification of in situ markers in tumors,...

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Autores principales: Venturoli, Carolina, Piga, Ilaria, Curtarello, Matteo, Verza, Martina, Esposito, Giovanni, Venuto, Santina, Navaglia, Filippo, Grassi, Angela, Indraccolo, Stefano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915933/
https://www.ncbi.nlm.nih.gov/pubmed/33562444
http://dx.doi.org/10.3390/cells10020325
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author Venturoli, Carolina
Piga, Ilaria
Curtarello, Matteo
Verza, Martina
Esposito, Giovanni
Venuto, Santina
Navaglia, Filippo
Grassi, Angela
Indraccolo, Stefano
author_facet Venturoli, Carolina
Piga, Ilaria
Curtarello, Matteo
Verza, Martina
Esposito, Giovanni
Venuto, Santina
Navaglia, Filippo
Grassi, Angela
Indraccolo, Stefano
author_sort Venturoli, Carolina
collection PubMed
description Pyruvate dehydrogenase kinase 1 (PDK1) blockade triggers are well characterized in vitro metabolic alterations in cancer cells, including reduced glycolysis and increased glucose oxidation. Here, by gene expression profiling and digital pathology-mediated quantification of in situ markers in tumors, we investigated effects of PDK1 silencing on growth, angiogenesis and metabolic features of tumor xenografts formed by highly glycolytic OC316 and OVCAR3 ovarian cancer cells. Notably, at variance with the moderate antiproliferative effects observed in vitro, we found a dramatic negative impact of PDK1 silencing on tumor growth. These findings were associated with reduced angiogenesis and increased necrosis in the OC316 and OVCAR3 tumor models, respectively. Analysis of viable tumor areas uncovered increased proliferation as well as increased apoptosis in PDK1-silenced OVCAR3 tumors. Moreover, RNA profiling disclosed increased glucose catabolic pathways—comprising both oxidative phosphorylation and glycolysis—in PDK1-silenced OVCAR3 tumors, in line with the high mitotic activity detected in the viable rim of these tumors. Altogether, our findings add new evidence in support of a link between tumor metabolism and angiogenesis and remark on the importance of investigating net effects of modulations of metabolic pathways in the context of the tumor microenvironment.
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spelling pubmed-79159332021-03-01 Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts Venturoli, Carolina Piga, Ilaria Curtarello, Matteo Verza, Martina Esposito, Giovanni Venuto, Santina Navaglia, Filippo Grassi, Angela Indraccolo, Stefano Cells Article Pyruvate dehydrogenase kinase 1 (PDK1) blockade triggers are well characterized in vitro metabolic alterations in cancer cells, including reduced glycolysis and increased glucose oxidation. Here, by gene expression profiling and digital pathology-mediated quantification of in situ markers in tumors, we investigated effects of PDK1 silencing on growth, angiogenesis and metabolic features of tumor xenografts formed by highly glycolytic OC316 and OVCAR3 ovarian cancer cells. Notably, at variance with the moderate antiproliferative effects observed in vitro, we found a dramatic negative impact of PDK1 silencing on tumor growth. These findings were associated with reduced angiogenesis and increased necrosis in the OC316 and OVCAR3 tumor models, respectively. Analysis of viable tumor areas uncovered increased proliferation as well as increased apoptosis in PDK1-silenced OVCAR3 tumors. Moreover, RNA profiling disclosed increased glucose catabolic pathways—comprising both oxidative phosphorylation and glycolysis—in PDK1-silenced OVCAR3 tumors, in line with the high mitotic activity detected in the viable rim of these tumors. Altogether, our findings add new evidence in support of a link between tumor metabolism and angiogenesis and remark on the importance of investigating net effects of modulations of metabolic pathways in the context of the tumor microenvironment. MDPI 2021-02-05 /pmc/articles/PMC7915933/ /pubmed/33562444 http://dx.doi.org/10.3390/cells10020325 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Venturoli, Carolina
Piga, Ilaria
Curtarello, Matteo
Verza, Martina
Esposito, Giovanni
Venuto, Santina
Navaglia, Filippo
Grassi, Angela
Indraccolo, Stefano
Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts
title Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts
title_full Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts
title_fullStr Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts
title_full_unstemmed Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts
title_short Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts
title_sort genetic perturbation of pyruvate dehydrogenase kinase 1 modulates growth, angiogenesis and metabolic pathways in ovarian cancer xenografts
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915933/
https://www.ncbi.nlm.nih.gov/pubmed/33562444
http://dx.doi.org/10.3390/cells10020325
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