Publications by authors named "Jan Pencik"

14 Publications

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A hydride transfer complex reprograms NAD metabolism and bypasses senescence.

Mol Cell 2021 09;81(18):3848-3865.e19

CRCHUM, 900 Saint-Denis St, Montréal, QC H2X 0A9, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada. Electronic address:

Metabolic rewiring and redox balance play pivotal roles in cancer. Cellular senescence is a barrier for tumorigenesis circumvented in cancer cells by poorly understood mechanisms. We report a multi-enzymatic complex that reprograms NAD metabolism by transferring reducing equivalents from NADH to NADP. This hydride transfer complex (HTC) is assembled by malate dehydrogenase 1, malic enzyme 1, and cytosolic pyruvate carboxylase. HTC is found in phase-separated bodies in the cytosol of cancer or hypoxic cells and can be assembled in vitro with recombinant proteins. HTC is repressed in senescent cells but induced by p53 inactivation. HTC enzymes are highly expressed in mouse and human prostate cancer models, and their inactivation triggers senescence. Exogenous expression of HTC is sufficient to bypass senescence, rescue cells from complex I inhibitors, and cooperate with oncogenic RAS to transform primary cells. Altogether, we provide evidence for a new multi-enzymatic complex that reprograms metabolism and overcomes cellular senescence.
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http://dx.doi.org/10.1016/j.molcel.2021.08.028DOI Listing
September 2021

Surface Characteristics of One-Sided Charred Beech Wood.

Polymers (Basel) 2021 May 12;13(10). Epub 2021 May 12.

Department of Wood Science and Technology, Faculty of Forestry and Wood Technology, Mendel University in Brno, Zemědělská 3, 613 00 Brno, Czech Republic.

The aim of this paper was to analyze selected properties of beech wood ( L.) treated by one-sided surface charring. Specimens were one-side charred with a hot plate using several time-temperature combinations (from 200 to 400 °C). Characteristics such as colour, discoloration, surface roughness, fire resistance, total carbohydrate content at several wood layers and decay resistance were evaluated. Surface charring was applied to the radial and tangential surfaces. Colour measurements showed that the surface of the wood turned grey due to charring. In addition to colour measurements, other experiments showed significant differences between radial and tangential specimens due to their different structures. The higher the temperature used in treating them, the lower the roughness values for radial specimens, while the trend for tangential specimens was the opposite. A smoother surface is more fire resistant, so radial specimens are generally better in this regard. Tangential specimens are more susceptible during preparation to forming cracks that impair flame resistance because a continuous protective densified layer is not formed. The determination of total carbohydrates revealed significant changes at various wood depths after surface charring. These changes were more predictable in radial specimens due to the annual ring orientation, because each layer consisted of a similar earlywood/latewood ratio. Finally, when decay resistance was assessed, weight loss was found to be lower in all specimens than in the references. The results suggest that charring at a particular combination of temperature and time improved the investigated properties of the surface-modified beech.
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http://dx.doi.org/10.3390/polym13101551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151175PMC
May 2021

Thyroid and androgen receptor signaling are antagonized by μ-Crystallin in prostate cancer.

Int J Cancer 2021 02 31;148(3):731-747. Epub 2020 Oct 31.

Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.

Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3'-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidences show a higher incidence of PCa in men with elevated thyroid hormone levels. The thyroid hormone binding protein μ-Crystallin (CRYM) mediates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TRα/TRβ) in target tissues. We show in our study that low CRYM expression levels in PCa patients are associated with early biochemical recurrence and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intracellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in positron emission tomography/magnetic resonance imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3- and androgen-mediated signaling in PCa. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth.
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http://dx.doi.org/10.1002/ijc.33332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756625PMC
February 2021

STAT3-dependent analysis reveals PDK4 as independent predictor of recurrence in prostate cancer.

Mol Syst Biol 2020 04;16(4):e9247

Department of Analytical Chemistry, University of Vienna, Vienna, Austria.

Prostate cancer (PCa) has a broad spectrum of clinical behavior; hence, biomarkers are urgently needed for risk stratification. Here, we aim to find potential biomarkers for risk stratification, by utilizing a gene co-expression network of transcriptomics data in addition to laser-microdissected proteomics from human and murine prostate FFPE samples. We show up-regulation of oxidative phosphorylation (OXPHOS) in PCa on the transcriptomic level and up-regulation of the TCA cycle/OXPHOS on the proteomic level, which is inversely correlated to STAT3 expression. We hereby identify gene expression of pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of the TCA cycle, as a promising independent prognostic marker in PCa. PDK4 predicts disease recurrence independent of diagnostic risk factors such as grading, staging, and PSA level. Therefore, low PDK4 is a promising marker for PCa with dismal prognosis.
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http://dx.doi.org/10.15252/msb.20199247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178451PMC
April 2020

STAT5BN642H is a driver mutation for T cell neoplasia.

J Clin Invest 2018 01 4;128(1):387-401. Epub 2017 Dec 4.

Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.

STAT5B is often mutated in hematopoietic malignancies. The most frequent STAT5B mutation, Asp642His (N642H), has been found in over 90 leukemia and lymphoma patients. Here, we used the Vav1 promoter to generate transgenic mouse models that expressed either human STAT5B or STAT5BN642H in the hematopoietic compartment. While STAT5B-expressing mice lacked a hematopoietic phenotype, the STAT5BN642H-expressing mice rapidly developed T cell neoplasms. Neoplasia manifested as transplantable CD8+ lymphoma or leukemia, indicating that the STAT5BN642H mutation drives cancer development. Persistent and enhanced levels of STAT5BN642H tyrosine phosphorylation in transformed CD8+ T cells led to profound changes in gene expression that were accompanied by alterations in DNA methylation at potential histone methyltransferase EZH2-binding sites. Aurora kinase genes were enriched in STAT5BN642H-expressing CD8+ T cells, which were exquisitely sensitive to JAK and Aurora kinase inhibitors. Together, our data suggest that JAK and Aurora kinase inhibitors should be further explored as potential therapeutics for lymphoma and leukemia patients with the STAT5BN642H mutation who respond poorly to conventional chemotherapy.
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http://dx.doi.org/10.1172/JCI94509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749501PMC
January 2018

A rare castration-resistant progenitor cell population is highly enriched in Pten-null prostate tumours.

J Pathol 2017 09 28;243(1):51-64. Epub 2017 Jul 28.

Institut Necker Enfants Malades (INEM), Inserm U1151-CNRS UMR 8253, University Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, Paris, France.

Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen deprivation remain poorly described, despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild-type (WT) mouse prostates a rare population of luminal progenitor cells that we called LSC according to their FACS profile (Lin /Sca-1 /CD49f ). Here, we investigated the prevalence and castration resistance of LSC in various mouse models of prostate tumourigenesis (Pb-PRL, Pten , and Hi-Myc mice). LSC prevalence is low (∼8%, similar to WT) in Hi-Myc mice, where prostatic androgen receptor signalling is unaltered, but is significantly higher in the two other models, where androgen receptor signalling is decreased, rising up to more than 80% in Pten prostates. LSC tolerate androgen deprivation and persist or are enriched 2-3 weeks after castration. The tumour-initiating properties of LSC from Pten mice were demonstrated by regeneration of tumours in vivo. Transcriptomic analysis revealed that LSC represent a unique cell entity as their gene expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signalling is markedly decreased, explaining why LSC tolerate androgen deprivation. This also illuminates why Pten tumours are castration-resistant since LSC represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSC on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSC in various mouse prostate specimens. In castrated Pten prostates, there was significant proliferation of CK4 cells, further demonstrating their key role in castration-resistant prostate cancer progression. Taken together, this study identifies LSC as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4924DOI Listing
September 2017

Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation.

Cell Death Dis 2016 10 13;7(10):e2419. Epub 2016 Oct 13.

Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.

Ewing sarcoma (ES) is the second most frequent childhood bone cancer driven by the EWS/FLI1 (EF) fusion protein. Genetically defined ES models are needed to understand how EF expression changes bone precursor cell differentiation, how ES arises and through which mechanisms of inhibition it can be targeted. We used mesenchymal Prx1-directed conditional EF expression in mice to study bone development and to establish a reliable sarcoma model. EF expression arrested early chondrocyte and osteoblast differentiation due to changed signaling pathways such as hedgehog, WNT or growth factor signaling. Mesenchymal stem cells (MSCs) expressing EF showed high self-renewal capacity and maintained an undifferentiated state despite high apoptosis. Blocking apoptosis through enforced BCL2 family member expression in MSCs promoted efficient and rapid sarcoma formation when transplanted to immunocompromised mice. Mechanistically, high BCL2 family member and CDK4, but low P53 and INK4A protein expression synergized in Ewing-like sarcoma development. Functionally, knockdown of Mcl1 or Cdk4 or their combined pharmacologic inhibition resulted in growth arrest and apoptosis in both established human ES cell lines and EF-transformed mouse MSCs. Combinatorial targeting of survival and cell cycle progression pathways could counteract this aggressive childhood cancer.
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http://dx.doi.org/10.1038/cddis.2016.268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133963PMC
October 2016

JAK-STAT signaling in cancer: From cytokines to non-coding genome.

Cytokine 2016 11 24;87:26-36. Epub 2016 Jun 24.

Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, Medical University of Vienna, 1090 Vienna, Austria; Department for Pathology of Laboratory Animals, University of Veterinary Medicine Vienna, 1210 Vienna, Austria. Electronic address:

In the past decades, studies of the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling have uncovered highly conserved programs linking cytokine signaling to the regulation of essential cellular mechanisms such as proliferation, invasion, survival, inflammation and immunity. Inhibitors of the JAK/STAT pathway are used for treatment of autoimmune diseases, such as rheumatoid arthritis or psoriasis. Aberrant JAK/STAT signaling has been identified to contribute to cancer progression and metastatic development. Targeting of JAK/STAT pathway is currently one of the most promising therapeutic strategies in prostate cancer (PCa), hematopoietic malignancies and sarcomas. Notably, newly identified regulators of JAK/STAT signaling, the non-coding RNAs transcripts and their role as important targets and potential clinical biomarkers are highlighted in this review. In addition to the established role of the JAK/STAT signaling pathway in traditional cytokine signaling the non-coding RNAs add yet another layer of hidden regulation and function. Understanding the crosstalk of non-coding RNA with JAK/STAT signaling in cancer is of critical importance and may result in better patient stratification not only in terms of prognosis but also in the context of therapy.
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http://dx.doi.org/10.1016/j.cyto.2016.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059362PMC
November 2016

Breaking a paradigm: IL-6/STAT3 signaling suppresses metastatic prostate cancer upon ARF expression.

Mol Cell Oncol 2016 Mar 4;3(2):e1090048. Epub 2016 Apr 4.

Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria; Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine Vienna, Vienna, Austria.

Interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling is considered to have important oncogenic functions in prostate cancer (PCa). However, a recent study highlighted the central role of IL-6/STAT3 signaling in regulation of the ARF-MDM2-p53 senescence axis. This reversal of the postulated oncogenic properties of IL-6/STAT3 signaling in PCa has important therapeutic implications.
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http://dx.doi.org/10.1080/23723556.2015.1090048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905394PMC
March 2016

IL-6/STAT3/ARF: the guardians of senescence, cancer progression and metastasis in prostate cancer.

Swiss Med Wkly 2015 21;145:w14215. Epub 2015 Dec 21.

Ludwig Boltzmann Institute for Cancer Research, Medical University of Vienna, Austria; Clinical Institute of Pathology, Medical University of Vienna, Austria; Depatment of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine Vienna, A.

Prostate cancer is one of the most prevalent forms of cancer in men worldwide. It remains a clinical challenge to identify lethal metastatic prostate cancers, which escape standard therapeutic intervention. Aberrant interleukin-6 (IL-6) / signal transducer and activator of transcription-3 (STAT3) signalling and loss of p53 occur during prostate cancer progression to metastatic disease. The abnormality of the IL-6/STAT3/p53 axis is frequently accompanied by other genetic alterations; however, its potential role as an important mediator of oncogenic reprogramming, invasion and metastatic transformation remains unknown. The failure of anti-IL-6 treatments is still unexplained and may be due to an incomplete understanding of the mechanism of the in vivo role of IL-6/STAT3 in prostate cancer. The identification of the alternative reading frame protein (ARF) / murine double minute protein (MDM2) / p53 tumour suppressor pathway potentially involving the IL-6/STAT3 axis as a restricting factor in prostate cancer deficient in the tumour suppressor phosphatase and tensin homologue (PTEN) opened new avenues to currently available therapies. This review summarises the current knowledge on the role of crucial pathways driving prostate cancer progression as well as metastatic disease and discusses the potential use of novel specific target molecules and how it can be exploited to avoid overtreatment and increase quality of life.
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http://dx.doi.org/10.4414/smw.2015.14215DOI Listing
September 2016

STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Nat Commun 2015 Jul 22;6:7736. Epub 2015 Jul 22.

Department of Pathology, University of Cambridge, CB2 0QQ Cambridge, UK.

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.
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http://dx.doi.org/10.1038/ncomms8736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525303PMC
July 2015
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