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

Int J Cancer. 2021 Feb 1;148(3):731-747. doi: 10.1002/ijc.33332. Epub 2020 Oct 31.


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.

Trial registration: NCT02659527.

Keywords: PSMA-PET; androgen receptor; prostate cancer; thyroid hormone receptor; μ-Crystallin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Choline / administration & dosage
  • Choline / analogs & derivatives
  • Cohort Studies
  • Crystallins / genetics*
  • Crystallins / metabolism*
  • Down-Regulation*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Metabolomics
  • Neoplasm Staging
  • PC-3 Cells
  • Positron Emission Tomography Computed Tomography
  • Prognosis
  • Prostatic Neoplasms / diagnostic imaging
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Receptors, Thyroid Hormone / genetics
  • Sequence Analysis, RNA
  • Signal Transduction*
  • Tissue Array Analysis
  • Triiodothyronine / antagonists & inhibitors
  • Triiodothyronine / metabolism
  • mu-Crystallins


  • AR protein, human
  • CRYM protein, human
  • Crystallins
  • Receptors, Androgen
  • Receptors, Thyroid Hormone
  • fluoromethylcholine
  • Triiodothyronine
  • mu-Crystallins
  • Choline

Associated data

  • EudraCT/2014-004758-33