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Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer

The mechanisms by which mitochondrial metabolism supports cancer anabolism are still unclear. Here, we unexpectedly find that genetic and pharmacological inactivation of Pyruvate Dehydrogenase A1 (PDHA1), a subunit of pyruvate dehydrogenase complex (PDC) inhibits prostate cancer development in diffe...

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Autores principales: Chen, Jingjing, Guccini, Ilaria, Di Mitri, Diletta, Brina, Daniela, Revandkar, Ajinkya, Sarti, Manuela, Pasquini, Emiliano, Alajati, Abdullah, Pinton, Sandra, Losa, Marco, Civenni, Gianluca, Catapano, Carlo V., Sgrignani, Jacopo, Cavalli, Andrea, D'Antuono, Rocco, Asara, John M., Morandi, Andrea, Chiarugi, Paola, Crotti, Sara, Agostini, Marco, Montopoli, Monica, Masgras, Ionica, Rasola, Andrea, Garcia-Escudero, Ramon, Delaleu, Nicolas, Rinaldi, Andrea, Bertoni, Francesco, de Bono, Johann, Carracedo, Arkaitz, Alimonti, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810912/
https://www.ncbi.nlm.nih.gov/pubmed/29335542
http://dx.doi.org/10.1038/s41588-017-0026-3
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author Chen, Jingjing
Guccini, Ilaria
Di Mitri, Diletta
Brina, Daniela
Revandkar, Ajinkya
Sarti, Manuela
Pasquini, Emiliano
Alajati, Abdullah
Pinton, Sandra
Losa, Marco
Civenni, Gianluca
Catapano, Carlo V.
Sgrignani, Jacopo
Cavalli, Andrea
D'Antuono, Rocco
Asara, John M.
Morandi, Andrea
Chiarugi, Paola
Crotti, Sara
Agostini, Marco
Montopoli, Monica
Masgras, Ionica
Rasola, Andrea
Garcia-Escudero, Ramon
Delaleu, Nicolas
Rinaldi, Andrea
Bertoni, Francesco
de Bono, Johann
Carracedo, Arkaitz
Alimonti, Andrea
author_facet Chen, Jingjing
Guccini, Ilaria
Di Mitri, Diletta
Brina, Daniela
Revandkar, Ajinkya
Sarti, Manuela
Pasquini, Emiliano
Alajati, Abdullah
Pinton, Sandra
Losa, Marco
Civenni, Gianluca
Catapano, Carlo V.
Sgrignani, Jacopo
Cavalli, Andrea
D'Antuono, Rocco
Asara, John M.
Morandi, Andrea
Chiarugi, Paola
Crotti, Sara
Agostini, Marco
Montopoli, Monica
Masgras, Ionica
Rasola, Andrea
Garcia-Escudero, Ramon
Delaleu, Nicolas
Rinaldi, Andrea
Bertoni, Francesco
de Bono, Johann
Carracedo, Arkaitz
Alimonti, Andrea
author_sort Chen, Jingjing
collection PubMed
description The mechanisms by which mitochondrial metabolism supports cancer anabolism are still unclear. Here, we unexpectedly find that genetic and pharmacological inactivation of Pyruvate Dehydrogenase A1 (PDHA1), a subunit of pyruvate dehydrogenase complex (PDC) inhibits prostate cancer development in different mouse and human xenograft tumour models by affecting lipid biosynthesis. Mechanistically, we show that in prostate cancer, PDC localizes in both mitochondria and nucleus. While nuclear PDC controls the expression of Sterol regulatory element-binding transcription factor (SREBF) target genes by mediating histone acetylation, mitochondrial PDC provides cytosolic citrate for lipid synthesis in a coordinated effort to sustain anabolism. In line with these evidence, we find that PDHA1 and the PDC activator, Pyruvate dehydrogenase phosphatase 1 (PDP1), are frequently amplified and overexpressed at both gene and protein level in prostate tumours. Taken together, these findings demonstrate that both mitochondrial and nuclear PDC sustain prostate tumourigenesis by controlling lipid biosynthesis thereby pointing at this complex as a novel target for cancer therapy.
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spelling pubmed-58109122018-07-15 Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer Chen, Jingjing Guccini, Ilaria Di Mitri, Diletta Brina, Daniela Revandkar, Ajinkya Sarti, Manuela Pasquini, Emiliano Alajati, Abdullah Pinton, Sandra Losa, Marco Civenni, Gianluca Catapano, Carlo V. Sgrignani, Jacopo Cavalli, Andrea D'Antuono, Rocco Asara, John M. Morandi, Andrea Chiarugi, Paola Crotti, Sara Agostini, Marco Montopoli, Monica Masgras, Ionica Rasola, Andrea Garcia-Escudero, Ramon Delaleu, Nicolas Rinaldi, Andrea Bertoni, Francesco de Bono, Johann Carracedo, Arkaitz Alimonti, Andrea Nat Genet Article The mechanisms by which mitochondrial metabolism supports cancer anabolism are still unclear. Here, we unexpectedly find that genetic and pharmacological inactivation of Pyruvate Dehydrogenase A1 (PDHA1), a subunit of pyruvate dehydrogenase complex (PDC) inhibits prostate cancer development in different mouse and human xenograft tumour models by affecting lipid biosynthesis. Mechanistically, we show that in prostate cancer, PDC localizes in both mitochondria and nucleus. While nuclear PDC controls the expression of Sterol regulatory element-binding transcription factor (SREBF) target genes by mediating histone acetylation, mitochondrial PDC provides cytosolic citrate for lipid synthesis in a coordinated effort to sustain anabolism. In line with these evidence, we find that PDHA1 and the PDC activator, Pyruvate dehydrogenase phosphatase 1 (PDP1), are frequently amplified and overexpressed at both gene and protein level in prostate tumours. Taken together, these findings demonstrate that both mitochondrial and nuclear PDC sustain prostate tumourigenesis by controlling lipid biosynthesis thereby pointing at this complex as a novel target for cancer therapy. 2018-01-15 2018-02 /pmc/articles/PMC5810912/ /pubmed/29335542 http://dx.doi.org/10.1038/s41588-017-0026-3 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Chen, Jingjing
Guccini, Ilaria
Di Mitri, Diletta
Brina, Daniela
Revandkar, Ajinkya
Sarti, Manuela
Pasquini, Emiliano
Alajati, Abdullah
Pinton, Sandra
Losa, Marco
Civenni, Gianluca
Catapano, Carlo V.
Sgrignani, Jacopo
Cavalli, Andrea
D'Antuono, Rocco
Asara, John M.
Morandi, Andrea
Chiarugi, Paola
Crotti, Sara
Agostini, Marco
Montopoli, Monica
Masgras, Ionica
Rasola, Andrea
Garcia-Escudero, Ramon
Delaleu, Nicolas
Rinaldi, Andrea
Bertoni, Francesco
de Bono, Johann
Carracedo, Arkaitz
Alimonti, Andrea
Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer
title Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer
title_full Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer
title_fullStr Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer
title_full_unstemmed Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer
title_short Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer
title_sort compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810912/
https://www.ncbi.nlm.nih.gov/pubmed/29335542
http://dx.doi.org/10.1038/s41588-017-0026-3
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