Heterogeneous Expression and Subcellular Localization of Pyruvate Dehydrogenase Complex in Prostate Cancer
BackgroundPyruvate dehydrogenase (PDH) complex converts pyruvate into acetyl-CoA by pyruvate decarboxylation, which drives energy metabolism during cell growth, including prostate cancer (PCa) cell growth. The major catalytic subunit of PDH, PDHA1, is regulated by phosphorylation/dephosphorylation b...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.873516/full |
| _version_ | 1811255758685208576 |
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| author | Caroline E. Nunes-Xavier Caroline E. Nunes-Xavier Janire Mingo Maite Emaldi Karine Flem-Karlsen Gunhild M. Mælandsmo Øystein Fodstad Roberto Llarena José I. López José I. López Rafael Pulido Rafael Pulido |
| author_facet | Caroline E. Nunes-Xavier Caroline E. Nunes-Xavier Janire Mingo Maite Emaldi Karine Flem-Karlsen Gunhild M. Mælandsmo Øystein Fodstad Roberto Llarena José I. López José I. López Rafael Pulido Rafael Pulido |
| author_sort | Caroline E. Nunes-Xavier |
| collection | DOAJ |
| description | BackgroundPyruvate dehydrogenase (PDH) complex converts pyruvate into acetyl-CoA by pyruvate decarboxylation, which drives energy metabolism during cell growth, including prostate cancer (PCa) cell growth. The major catalytic subunit of PDH, PDHA1, is regulated by phosphorylation/dephosphorylation by pyruvate dehydrogenase kinases (PDKs) and pyruvate dehydrogenase phosphatases (PDPs). There are four kinases, PDK1, PDK2, PDK3 and PDK4, which can phosphorylate and inactivate PDH; and two phosphatases, PDP1 and PDP2, that dephosphorylate and activate PDH.MethodsWe have analyzed by immunohistochemistry the expression and clinicopathological correlations of PDHA1, PDP1, PDP2, PDK1, PDK2, PDK3, and PDK4, as well as of androgen receptor (AR), in a retrospective PCa cohort of patients. A total of 120 PCa samples of representative tumor areas from all patients were included in tissue microarray (TMA) blocks for analysis. In addition, we studied the subcellular localization of PDK2 and PDK3, and the effects of the PDK inhibitor dichloroacetate (DCA) in the growth, proliferation, and mitochondrial respiration of PCa cells.ResultsWe found heterogeneous expression of the PDH complex components in PCa tumors. PDHA1, PDP1, PDK1, PDK2, and PDK4 expression correlated positively with AR expression. A significant correlation of PDK2 immunostaining with biochemical recurrence and disease-free survival was revealed. In PCa tissue specimens, PDK2 displayed cytoplasmic and nuclear immunostaining, whereas PDK1, PDK3 and PDK4 showed mostly cytoplasmic staining. In cells, ectopically expressed PDK2 and PDK3 were mainly localized in mitochondria compartments. An increase in maximal mitochondrial respiration was observed in PCa cells upon PDK inhibition by DCA, in parallel with less proliferative capacity.ConclusionOur findings support the notion that expression of specific PDH complex components is related with AR signaling in PCa tumors. Furthermore, PDK2 expression associated with poor PCa prognosis. This highlights a potential for PDH complex components as targets for intervention in PCa. |
| first_indexed | 2024-04-12T17:29:44Z |
| format | Article |
| id | doaj.art-060cb01a32194d9ab44dea2f0e95b000 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T17:29:44Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-060cb01a32194d9ab44dea2f0e95b0002022-12-22T03:23:10ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-05-011210.3389/fonc.2022.873516873516Heterogeneous Expression and Subcellular Localization of Pyruvate Dehydrogenase Complex in Prostate CancerCaroline E. Nunes-Xavier0Caroline E. Nunes-Xavier1Janire Mingo2Maite Emaldi3Karine Flem-Karlsen4Gunhild M. Mælandsmo5Øystein Fodstad6Roberto Llarena7José I. López8José I. López9Rafael Pulido10Rafael Pulido11Biomarkers in Cancer, Biocruces Bizkaia Health Research Institute, Barakaldo, SpainDepartment of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, NorwayBiomarkers in Cancer, Biocruces Bizkaia Health Research Institute, Barakaldo, SpainBiomarkers in Cancer, Biocruces Bizkaia Health Research Institute, Barakaldo, SpainDepartment of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, NorwayDepartment of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, NorwayDepartment of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, NorwayDepartment of Urology, Cruces University Hospital, Barakaldo, SpainBiomarkers in Cancer, Biocruces Bizkaia Health Research Institute, Barakaldo, SpainDepartment of Pathology, Cruces University Hospital, Barakaldo, SpainBiomarkers in Cancer, Biocruces Bizkaia Health Research Institute, Barakaldo, SpainIkerbasque, Basque Foundation for Science, Bilbao, SpainBackgroundPyruvate dehydrogenase (PDH) complex converts pyruvate into acetyl-CoA by pyruvate decarboxylation, which drives energy metabolism during cell growth, including prostate cancer (PCa) cell growth. The major catalytic subunit of PDH, PDHA1, is regulated by phosphorylation/dephosphorylation by pyruvate dehydrogenase kinases (PDKs) and pyruvate dehydrogenase phosphatases (PDPs). There are four kinases, PDK1, PDK2, PDK3 and PDK4, which can phosphorylate and inactivate PDH; and two phosphatases, PDP1 and PDP2, that dephosphorylate and activate PDH.MethodsWe have analyzed by immunohistochemistry the expression and clinicopathological correlations of PDHA1, PDP1, PDP2, PDK1, PDK2, PDK3, and PDK4, as well as of androgen receptor (AR), in a retrospective PCa cohort of patients. A total of 120 PCa samples of representative tumor areas from all patients were included in tissue microarray (TMA) blocks for analysis. In addition, we studied the subcellular localization of PDK2 and PDK3, and the effects of the PDK inhibitor dichloroacetate (DCA) in the growth, proliferation, and mitochondrial respiration of PCa cells.ResultsWe found heterogeneous expression of the PDH complex components in PCa tumors. PDHA1, PDP1, PDK1, PDK2, and PDK4 expression correlated positively with AR expression. A significant correlation of PDK2 immunostaining with biochemical recurrence and disease-free survival was revealed. In PCa tissue specimens, PDK2 displayed cytoplasmic and nuclear immunostaining, whereas PDK1, PDK3 and PDK4 showed mostly cytoplasmic staining. In cells, ectopically expressed PDK2 and PDK3 were mainly localized in mitochondria compartments. An increase in maximal mitochondrial respiration was observed in PCa cells upon PDK inhibition by DCA, in parallel with less proliferative capacity.ConclusionOur findings support the notion that expression of specific PDH complex components is related with AR signaling in PCa tumors. Furthermore, PDK2 expression associated with poor PCa prognosis. This highlights a potential for PDH complex components as targets for intervention in PCa.https://www.frontiersin.org/articles/10.3389/fonc.2022.873516/fullprostate cancer (PCa)pyruvate dehydrogenase (PDH)pyruvate dehydrogenase kinase (PDK)androgen receptor (AR)dichloroacetate (DCA) |
| spellingShingle | Caroline E. Nunes-Xavier Caroline E. Nunes-Xavier Janire Mingo Maite Emaldi Karine Flem-Karlsen Gunhild M. Mælandsmo Øystein Fodstad Roberto Llarena José I. López José I. López Rafael Pulido Rafael Pulido Heterogeneous Expression and Subcellular Localization of Pyruvate Dehydrogenase Complex in Prostate Cancer Frontiers in Oncology prostate cancer (PCa) pyruvate dehydrogenase (PDH) pyruvate dehydrogenase kinase (PDK) androgen receptor (AR) dichloroacetate (DCA) |
| title | Heterogeneous Expression and Subcellular Localization of Pyruvate Dehydrogenase Complex in Prostate Cancer |
| title_full | Heterogeneous Expression and Subcellular Localization of Pyruvate Dehydrogenase Complex in Prostate Cancer |
| title_fullStr | Heterogeneous Expression and Subcellular Localization of Pyruvate Dehydrogenase Complex in Prostate Cancer |
| title_full_unstemmed | Heterogeneous Expression and Subcellular Localization of Pyruvate Dehydrogenase Complex in Prostate Cancer |
| title_short | Heterogeneous Expression and Subcellular Localization of Pyruvate Dehydrogenase Complex in Prostate Cancer |
| title_sort | heterogeneous expression and subcellular localization of pyruvate dehydrogenase complex in prostate cancer |
| topic | prostate cancer (PCa) pyruvate dehydrogenase (PDH) pyruvate dehydrogenase kinase (PDK) androgen receptor (AR) dichloroacetate (DCA) |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.873516/full |
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