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.

Center for Biomarker Research in Medicine Graz Austria

Center of Molecular Medicine Central European Institute of Technology Masaryk University Brno Czech Republic

Christian Doppler Laboratory for Applied Metabolomics Medical University of Vienna Vienna Austria

Department for Pharmaceutical Technology and Biopharmaceutics University of Vienna Vienna Austria

Department of Biomedical Imaging and Image Guided Therapy Medical University Vienna Vienna Austria

Department of Laboratory Medicine Medical University Vienna Vienna Austria

Department of Molecular Sciences Uppsala BioCenter Swedish University of Agricultural Sciences Uppsala Sweden

Department of Pathology Medical University Vienna Vienna Austria

Department of Pathology Rudolfinerhaus Privatklinik Gmbh Vienna Austria

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Innsbruck Medical University Innsbruck Austria

Department of Urology Medical University Vienna Vienna Austria

Department of Urology University of Texas Southwestern Dallas Texas USA

Departments of Urology Weill Cornell Medical College New York New York USA

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Cambridge UK

Division of Urology Department of Special Surgery Jordan University Hospital The University of Jordan Amman Jordan

Histo Consulting Inc Ulm Germany

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

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

Ludwig Boltzmann Institute Applied Diagnostics Vienna Austria

MLL Munich Leukemia Laboratory Munich Germany

Present address Jan Pencik Molecular and Cell Biology Laboratory The Salk Institute for Biological Studies La Jolla California USA

School of Pharmacy University of Nottingham Nottingham UK

Unit for Laboratory Animal Pathology University of Veterinary Medicine Vienna Vienna Austria

Zobrazit více v PubMed

Huggins C, Hodges CV. Studies on prostate cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatase in metastatic carcinoma of the prostate. Cancer Res. 1941;1:239‐297. PubMed

Porkka KP, Visakorpi T. Molecular mechanisms of prostate cancer. Eur Urol. 2004;45(6):683‐691. PubMed

Haile S, Sadar MD. Androgen receptor and its splice variants in prostate cancer. Cell Mol Life Sci. 2011;68(24):3971‐3981. PubMed PMC

Watson PA, Chen YF, Balbas MD, et al. Constitutively active androgen receptor splice variants expressed in castration‐resistant prostate cancer require full‐length androgen receptor. Proc Natl Acad Sci U S A. 2010;107(39):16759‐16765. PubMed PMC

Visser WE, Wong WS, van Mullem AA, Friesema EC, Geyer J, Visser TJ. Study of the transport of thyroid hormone by transporters of the SLC10 family. Mol Cell Endocrinol. 2010;315(1‐2):138‐145. PubMed

Bernal J, Guadano‐Ferraz A, Morte B. Thyroid hormone transporters‐functions and clinical implications. Nat Rev Endocrinol. 2015;11(12):690. PubMed

Vie MP, Evrard C, Osty J, et al. Purification, molecular cloning, and functional expression of the human nicodinamide‐adenine dinucleotide phosphate‐regulated thyroid hormone‐binding protein. Mol Endocrinol. 1997;11(11):1728‐1736. PubMed

Kim RY, Gasser R, Wistow GJ. mu‐crystallin is a mammalian homologue of Agrobacterium ornithine cyclodeaminase and is expressed in human retina. Proc Natl Acad Sci U S A. 1992;89(19):9292‐9296. PubMed PMC

Shukla‐Dave A, Castillo‐Martin M, Chen M, et al. Ornithine decarboxylase is sufficient for prostate tumorigenesis via androgen receptor signaling. Am J Pathol. 2016;186(12):3131‐3145. PubMed PMC

Moeller LC, Fuhrer D. Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective. Endocr Relat Cancer. 2013;20(2):R19‐R29. PubMed

Suzuki S, Mori J, Hashizume K. mu‐crystallin, a NADPH‐dependent T(3)‐binding protein in cytosol. Trends Endocrinol Metab. 2007;18(7):286‐289. PubMed

Malinowska K, Cavarretta IT, Susani M, et al. Identification of mu‐crystallin as an androgen‐regulated gene in human prostate cancer. Prostate. 2009;69(10):1109‐1118. PubMed

Mousses S, Bubendorf L, Wagner U, et al. Clinical validation of candidate genes associated with prostate cancer progression in the CWR22 model system using tissue microarrays. Cancer Res. 2002;62(5):1256‐1260. PubMed

Schlederer M, Mueller KM, Haybaeck J, et al. Reliable quantification of protein expression and cellular localization in histological sections. PLoS One. 2014;9(7):e100822. PubMed PMC

Pencik J, Schlederer M, Gruber W, et al. STAT3 regulated ARF expression suppresses prostate cancer metastasis. Nat Commun. 2015;6:7736. PubMed PMC

Moazzami AA, Andersson R, Kamal‐Eldin A. Changes in the metabolic profile of rat liver after alpha‐tocopherol deficiency as revealed by metabolomics analysis. NMR Biomed. 2011;24(5):499‐505. PubMed

Moazzami AA, Shrestha A, Morrison DA, Poutanen K, Mykkanen H. Metabolomics reveals differences in postprandial responses to breads and fasting metabolic characteristics associated with postprandial insulin demand in postmenopausal women. J Nutr. 2014;144(6):807‐814. PubMed

Proestling K, Hebar A, Pruckner N, Marton E, Vinatzer U, Schreiber M. The Pro allele of the p53 codon 72 polymorphism is associated with decreased intratumoral expression of BAX and p21, and increased breast cancer risk. PLoS One. 2012;7(10):e47325. PubMed PMC

Rhodes DR, Yu J, Shanker K, et al. ONCOMINE: a cancer microarray database and integrated data‐mining platform. Neoplasia. 2004;6(1):1‐6. PubMed PMC

Sadow PM, Chassande O, Koo EK, et al. Regulation of expression of thyroid hormone receptor isoforms and coactivators in liver and heart by thyroid hormone. Mol Cell Endocrinol. 2003;203(1‐2):65‐75. PubMed

Baron A, Migita T, Tang D, Loda M. Fatty acid synthase: a metabolic oncogene in prostate cancer? J Cell Biochem. 2004;91(1):47‐53. PubMed

Zadra G, Ribeiro CF, Chetta P, et al. Inhibition of de novo lipogenesis targets androgen receptor signaling in castration‐resistant prostate cancer. Proc Natl Acad Sci U S A. 2019;116(2):631‐640. PubMed PMC

Malinen M, Niskanen EA, Kaikkonen MU, Palvimo JJ. Crosstalk between androgen and pro‐inflammatory signaling remodels androgen receptor and NF‐kappaB cistrome to reprogram the prostate cancer cell transcriptome. Nucleic Acids Res. 2017;45(2):619‐630. PubMed PMC

Aoyama C, Liao H, Ishidate K. Structure and function of choline kinase isoforms in mammalian cells. Prog Lipid Res. 2004;43(3):266‐281. PubMed

Morigi JJ, Stricker PD, van Leeuwen PJ, et al. Prospective comparison of 18F‐fluoromethylcholine versus 68Ga‐PSMA PET/CT in prostate cancer patients who have rising PSA after curative treatment and are being considered for targeted therapy. J Nucl Med. 2015;56(8):1185‐1190. PubMed

Ohkubo Y, Sekido T, Nishio SI, et al. Loss of mu‐crystallin causes PPARγ activation and obesity in high‐fat diet‐fed mice. Biochem Biophys Res Commun. 2019;508(3):914‐920. PubMed

Mishra S, Tai Q, Gu X, et al. Estrogen and estrogen receptor alpha promotes malignancy and osteoblastic tumorigenesis in prostate cancer. Oncotarget. 2015;6(42):44388‐44402. PubMed PMC

Yu L, Shi J, Cheng S, et al. Estrogen promotes prostate cancer cell migration via paracrine release of ENO1 from stromal cells. Mol Endocrinol. 2012;26(9):1521‐1530. PubMed PMC

Khan SR, Chaker L, Ruiter R, et al. Thyroid function and cancer risk: the Rotterdam study. J Clin Endocrinol Metab. 2016;101(12):5030‐5036. PubMed

Suzuki S, Takei M, Nishio S, et al. Spiking expression of mu‐crystallin mRNA during treatment with methimazole in patients with graves' hyperthyroidism. Horm Metab Res. 2009;41(7):548‐553. PubMed

Arlauckas SP, Popov AV, Delikatny EJ. Choline kinase alpha‐putting the ChoK‐hold on tumor metabolism. Prog Lipid Res. 2016;63:28‐40. PubMed PMC

Swanson MG, Keshari KR, Tabatabai ZL, et al. Quantification of choline‐ and ethanolamine‐containing metabolites in human prostate tissues using 1H HR‐MAS total correlation spectroscopy. Magn Reson Med. 2008;60(1):33‐40. PubMed PMC

Asim M, Massie CE, Orafidiya F, et al. Choline kinase alpha as an androgen receptor chaperone and prostate cancer therapeutic target. J Natl Cancer Inst. 2016;108(5):1‐13. PubMed PMC

Contractor K, Challapalli A, Barwick T, et al. Use of [11C]choline PET‐CT as a noninvasive method for detecting pelvic lymph node status from prostate cancer and relationship with choline kinase expression. Clin Cancer Res. 2011;17(24):7673‐7683. PubMed

Hartenbach M, Hartenbach S, Bechtloff W, et al. Combined PET/MRI improves diagnostic accuracy in patients with prostate cancer: a prospective diagnostic trial. Clin Cancer Res. 2014;20(12):3244‐3253. PubMed

Cristofanilli M, Yamamura Y, Kau SW, et al. Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated with a reduced incidence of primary breast carcinoma. Cancer. 2005;103(6):1122‐1128. PubMed

Mishkin SY, Pollack R, Yalovsky MA, Morris HP, Mishkin S. Inhibition of local and metastatic hepatoma growth and prolongation of survival after induction of hypothyroidism. Cancer Res. 1981;41(8):3040‐3045. PubMed

Lim W, Nguyen NH, Yang HY, Scanlan TS, Furlow JD. A thyroid hormone antagonist that inhibits thyroid hormone action in vivo. J Biol Chem. 2002;277(38):35664‐35670. PubMed

Hiroi Y, Kim HH, Ying H, et al. Rapid nongenomic actions of thyroid hormone. Proc Natl Acad Sci U S A. 2006;103(38):14104‐14109. PubMed PMC

A novel assessment of whole-mount Gleason grading in prostate cancer to identify candidates for radical prostatectomy: a machine learning-based multiomics study

Zobrazit více v PubMed

ClinicalTrials.gov
NCT02659527

EudraCT
2014-004758-33