<i><scp>STAT</scp>3</i>‐dependent analysis reveals<i><scp>PDK</scp>4</i>as independent predictor of recurrence in prostate cancer

Oberhuber, Monika; Pecoraro, Matteo; Rusz, Mate; Oberhuber, Georg; Wieselberg, Maritta; Haslinger, Peter; Gurnhofer, Elisabeth; Schlederer, Michaela; Limberger, Tanja; Lagger, Sabine; Pěnčík, Jan; Kodajova, Petra; Högler, Sandra; Stockmaier, Georg; Grund-Gröschke, Sandra; Aberger, Fritz; Bolis, Marco; Theurillat, Jean-Philippe; Wiebringhaus, Robert; Weiss, Theresa R.; Haitel, Andrea; Brehme, Marc; Wadsak, Wolfgang; Griss, Johannes; Mohr, Thomas; Hofer, Alexandra; Jäger, Anton; Pollheimer, Jürgen; Egger, Gerda; Koellensperger, Gunda; Mann, Matthias; Hantusch, Brigitte; Kenner, Lukas

doi:10.15252/msb.20199247

Cited by 45 publications

(23 citation statements)

References 122 publications

(188 reference statements)

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“…Since low levels of PDK4 result in enhanced OXPHOS and/or enhanced lipogenesis, both of which are associated with poor prognosis in PCa, PDK4 should have a tumor suppressive effect in primary PCa. Recently, a protective effect of high PDK4expression in PCa in a transcriptomic patient dataset was demonstrated (63). In accordance with these data, augmented gene expression and protein levels of the PDC subunit E1 (PDHA1) and the PDC activator PDP1 were identified in PCa (86) increased apoptosis in PCa cells upon knockdown of all PDK isoforms (40).…”

Section: The Peculiar Energy Metabolism Of Pca and Its Implications Omentioning

confidence: 63%

The Implications of PDK1–4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance

2020

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A metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis—known as the Warburg effect—is characteristic for many cancers. It gives the cancer cells a survival advantage in the hypoxic tumor microenvironment and protects them from cytotoxic effects of oxidative damage and apoptosis. The main regulators of this metabolic shift are the pyruvate dehydrogenase complex and pyruvate dehydrogenase kinase (PDK) isoforms 1–4. PDK is known to be overexpressed in several cancers and is associated with bad prognosis and therapy resistance. Whereas the expression of PDK1–3 is tissue specific, PDK4 expression is dependent on the energetic state of the whole organism. In contrast to other PDK isoforms, not only oncogenic, but also tumor suppressive functions of PDK4 have been reported. In tumors that profit from high OXPHOS and high de novo fatty acid synthesis, PDK4 can have a protective effect. This is the case for prostate cancer, the most common cancer in men, and makes PDK4 an interesting therapeutic target. While most work is focused on PDK in tumors characterized by high glycolytic activity, little research is devoted to those cases where PDK4 acts protective and is therefore highly needed.

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Section: The Peculiar Energy Metabolism Of Pca and Its Implications Omentioning

confidence: 63%

The Implications of PDK1–4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance

2020

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“…N-acylethanolamine acid amidase and protein tyrosine kinase 7 were shown to be markers for aggressive prostate cancer [ 54 ]. Pyruvate dehydrogenase kinase 4 (PDK4) could also be a potential prognostic target in prostate cancer [ 61 ]. High expression of MVP was found to be associated with poorer survival in PCa patients [ 62 ].…”

Section: Proteomes Of Clinical Prostate Cancer Samplesmentioning

confidence: 99%

Proteomic Landscape of Prostate Cancer: The View Provided by Quantitative Proteomics, Integrative Analyses, and Protein Interactomes

Sadeesh

Scaravilli

Latonen

2021

Cancers

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Prostate cancer is the second most frequent cancer of men worldwide. While the genetic landscapes and heterogeneity of prostate cancer are relatively well-known already, methodological developments now allow for studying basic and dynamic proteomes on a large scale and in a quantitative fashion. This aids in revealing the functional output of cancer genomes. It has become evident that not all aberrations at the genetic and transcriptional level are translated to the proteome. In addition, the proteomic level contains heterogeneity, which increases as the cancer progresses from primary prostate cancer (PCa) to metastatic and castration-resistant prostate cancer (CRPC). While multiple aspects of prostate adenocarcinoma proteomes have been studied, less is known about proteomes of neuroendocrine prostate cancer (NEPC). In this review, we summarize recent developments in prostate cancer proteomics, concentrating on the proteomic landscapes of clinical prostate cancer, cell line and mouse model proteomes interrogating prostate cancer-relevant signaling and alterations, and key prostate cancer regulator interactomes, such as those of the androgen receptor (AR). Compared to genomic and transcriptomic analyses, the view provided by proteomics brings forward changes in prostate cancer metabolism, post-transcriptional RNA regulation, and post-translational protein regulatory pathways, requiring the full attention of studies in the future.

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“…PDK 1–3 functions as an oncogene by interacting with numerous signaling pathways that contribute in cancer growth. PDK4’s function is multifaceted, since it functions as both an oncogene and a tumor suppressor ( 15 ). PDK3 has highest affinity to the PDC and is least researched ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Pyruvate Dehydrogenase Kinase-3 Predicts Poor Prognosis in Urothelial Carcinoma

et al. 2021

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BackgroundThe mitochondrial pyruvate dehydrogenase complex (PDC) link glycolysis to the tricarboxylic acid cycle by decarboxylating pyruvate to acetyl coenzyme A irreversibly. Cancer cells are characterized by a shift in cellular metabolism from mitochondrial respiration to glycolysis. PDC activity inhibition mediated by phosphorylation via pyruvate dehydrogenase kinase (PDK) has been linked to cancer. However, the clinical significance of PDKs in urothelial cancer prognosis is not clear. We investigated the role and prognostic value of PDK3 expression in patients with upper urinary tract urothelial carcinoma (UTUC) and urinary bladder urothelial carcinoma (UBUC).Patients and MethodsWe retrospectively analyzed clinical data and pathological features. Formalin-fixed urothelial carcinoma (UC) tissues were collected and embedded in paraffin. The correlation of PDK3 expression with clinical characteristics, pathological findings and patient outcomes, including metastasis-free survival (MFS) and disease-specific survival (DSS) were analyzed by Pearson’s chi-square test, Kaplan–Meier analysis, and the multivariate Cox proportional hazards model.ResultsData from 295 patients with UBUC and 340 patients with UTUC were evaluated. High PDK3 expression significantly correlated with several pathologic variables such as high T stage, lymph node metastases, high tumor grade, vascular invasion, and high mitotic rate (all P < 0.001). High PDK3 expression was associated with poor disease-specific survival (DSS) (P < 0.0001) and metastatic free survival (MFS) (P < 0.0001) in a Kaplan–Meier analysis. Additionally, multivariate analysis demonstrated increased PDK3 expression is a significant predictive risk factor for DSS [hazard ratio (HR) in UBUC, 2.79, P = 0.009; in UTUC, 2.561, P = 0.03] and MFS (HR in UBUC, 1.907, P = 0.024; in UTUC, 1.793, P = 0.044). The gene co-expression analysis showed abundant PDK3 co-upregulated genes were involved in the processes of DNA replication and repair through the Gene Ontology classification system.ConclusionHigh PDK3 expression has been linked to negative pathologic characteristics and poor oncological outcomes, suggesting that it could be used as a predictive biomarker for UC. PDK3 mRNA levels and its co-upregulated genes were strongly associated with DNA replication and repair. These results suggest that PDK3 may play a key role in tumor proliferation and development.

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STAT3‐dependent analysis revealsPDK4as independent predictor of recurrence in prostate cancer

Cited by 45 publications

References 122 publications

The Implications of PDK1–4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance

The Implications of PDK1–4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance

Proteomic Landscape of Prostate Cancer: The View Provided by Quantitative Proteomics, Integrative Analyses, and Protein Interactomes

Overexpression of Pyruvate Dehydrogenase Kinase-3 Predicts Poor Prognosis in Urothelial Carcinoma

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