The metastasis suppressor NDRG1 directly regulates androgen receptor signaling in prostate cancer

J Biol Chem. 2021 Dec;297(6):101414. doi: 10.1016/j.jbc.2021.101414. Epub 2021 Nov 14.

Abstract

N-myc-downregulated gene 1 (NDRG1) has potent anticancer effects and inhibits cell growth, survival, metastasis, and angiogenesis. Previous studies suggested that NDRG1 is linked to the androgen signaling network, but this mechanistic relationship is unclear. Considering the crucial role of the androgen receptor (AR) in prostate cancer (PCa) progression, here we examined for the first time the effect of NDRG1 on AR expression, activation, and downstream signaling in LNCaP, 22Rv1, and C4-2B PCa cell types. We demonstrate that NDRG1 effectively promotes interaction of AR with the chaperone HSP90, which in turn stabilizes the AR while decreasing its androgen-mediated activation. The expression of NDRG1 suppressed: (1) AR activation, as measured by p-ARSer213 and p-ARSer81; (2) expression of a major AR transcriptional target, prostate-specific antigen (PSA); and (3) AR transcriptional activity, probably via inhibiting the c-Jun-AR interaction by reducing c-Jun phosphorylation (p-c-JunSer63). NDRG1 was also demonstrated to inhibit multiple key molecules involved in androgen-dependent and -independent signaling (namely EGFR, HER2, HER3, PI3K, STAT3, and NF-κB), which promote the development of castration-resistant prostate cancer. We also identified the cysteine-rich secretory protein/antigen 5/pathogenesis related-1 (CAP) domain of NDRG1 as vital for inhibition of AR activity. Examining NDRG1 and p-NDRG1 in PCa patient specimens revealed a significant negative correlation between NDRG1 and PSA levels in prostatectomy patients that went on to develop metastasis. These results highlight a vital role for NDRG1 in androgen signaling and its potential as a key therapeutic target and biomarker in PCa.

Keywords: NDRG1; PSA; androgen receptor; prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Neoplasm Metastasis
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Signal Transduction*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • N-myc downstream-regulated gene 1 protein
  • Receptors, Androgen
  • Tumor Suppressor Proteins