Heterogeneous Expression and Subcellular Localization of Pyruvate Dehydrogenase Complex in Prostate Cancer

Abstract

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.

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

“…Whether high expression of PDK2 and PDK3 in ccRCC may have oncogenic consequences or may be an effect of early oncogenic metabolic reprogramming is currently unknown. We observed a difference in the subcellular localization of PDK2 and PDK3 proteins in ccRCC specimens, with PDK2 displaying enriched nuclear localization, similar to previously observed patterns in prostate cancer 43 . This could indicate a differential spatial role of the TCA cycle in cancer 44 , 45 .…”

“…DCA also increased pAKT content in ccRCC cells, reinforcing the correlation observed between PDK2/PDK3 and PI3K signalling pathway. Nevertheless, since DCA also inhibits PDK1 48 , whose expression was associated with better prognosis in our cohort, a differential contribution of PDK1-4 inhibition in ccRCC growth inhibition is expected, as it has also been proposed for other cancers 43 , 49 .…”

Regulation and tumor‐suppressive function of the miR‐379/miR‐656 (C14MC) cluster in cervical cancer

“…PDK3 , located at Xp22.11, encodes a 46.93 kDa pyruvate dehydrogenase kinase protein and is a key enzyme that controls glucose metabolism by connecting glycolysis with the tricarboxylic acid (TCA) cycle [ 81 ]. PDK3 is upregulated in colon [ 82 ], gastric [ 83 ], and prostate cancer [ 84 ]. Overexpression of PDK3 is associated with poor prognosis in a few cancers [ 85 ].…”

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

“…Beyond MPCs, the metabolic switch between glycolysis and mitochondrial oxidation is facilitated by the pyruvate dehydrogenase complex, its inhibitory phosphorylation by associated kinases, and opposing phosphatases (i.e., pyruvate dehydrogenase kinases [PDKs] and pyruvate dehydrogenase phosphatase catalytic subunit 1 [PDP1]) [ 151 ]. They are implicated during PCa progression and play a critical role in modulating acetyl-CoA production [ 152 , 153 , 154 , 155 ]. Increased PDHA1 and PDP1 activities have been shown to enhance PDK activity, lipogenesis, and glutamine dependence in PCa [ 156 , 157 ].…”