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

Osman Aksoy,Markus Hartenbach,Christopher J Roberts,Ali A Moazzami,Markus Mitterhauser,Georg Greiner,Lukas Kenner,Merima Herac,Judith Stangl‐Kremser,Andrea Haitel,Sabrina Hartenbach,Gerda Egger,Simone Tangermann,Shahrokh F Shariat,Bismoy Mazumder,Theresa Balber,Richard Moriggl,Jonathan B Whitchurch,Michaela Schlederer,David M Heery,Gero Kramer,Adam Varady,Heidi A Neubauer,Olaf Merkel,Gregor Hoermann,Melanie R Hassler,Martin Susani,Rodrig Marculescu,Jan Oppelt,Marcus Hacker,Boris Tichý ,Zoran Čulig ,Cécile Philippe ,Jan Pěnčík ,Suzanne Turner ,Pascal Baltzer ,Šárka Posp̂íšilová

doi:10.1002/ijc.33332

Abstract

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.

Highlights

prostate cancer (PCa) is the most frequently diagnosed cancer in men in the Western world
Decreased protein expression of CRYM was observed in PCa patient samples (n=178) compared to normal prostate glands (n=178), and a further reduction in CRYM expression was observed in metastatic samples (n=17, Figure 1A)
We investigated the crosstalk of CRYM with T3 and androgen receptor (AR) signalling in PCa

Summary

Introduction

PCa is the most frequently diagnosed cancer in men in the Western world. The course of PCa is largely driven by androgen receptor (AR) and, androgen ablation therapy is a cornerstone of current therapies[1, 2]. A large proportion of patients with advanced PCa become resistant to ADT resulting in lethal castration resistant prostate cancer (CRPC). The role thyroid hormone thyroxine (T4) and its more active form 3,5,3'-triiodo-L-thyronine (T3) in the progression of PCa has not been comprehensively elucidated. Intracellular thyroid hormone function in the prostate is dependent on CRYM expression levels [8, 9]. It was shown that CRYM expression is low in therapy refractory PCa patient biopsies [11]. We corroborated this finding and showed that CRYM is responsive to androgens in the MDA PCa 2b cell line [10]

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