The metastasis suppressor NDRG1 directly regulates androgen receptor signaling in prostate cancer
| Autor: | Syer C. Lim, Des R. Richardson, Sanaz Maleki, Bekesho Geleta, Žaklina Kovačević |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
STAT3 signal transducer and activator of transcription 3 S.E.M standard error of the mean HDAC histone deacetylase Cell Cycle Proteins urologic and male genital diseases NF-κB nuclear factor kappa light chain enhancer of activated B cells Biochemistry Metastasis PSA Prostate cancer T testosterone androgen receptor Neoplasm Metastasis IL-6 interleukin-6 PSA prostate-specific antigen biology ARE androgen response element Chemistry CRPC castration-resistant prostate cancer Intracellular Signaling Peptides and Proteins CAP cysteine-rich secretory protein/antigen 5/pathogenesis related-1 ELISA enzyme-linked immunosorbent assay prostate cancer Hsp90 CRISPR clustered regularly interspaced short palindromic repeats GAPDH glyceraldehyde-3-phosphate dehydrogenase Receptors Androgen JAK Janus kinase IHC immunohistochemistry PI3K phosphoinositide 3-kinase Research Article Signal Transduction DAPI 4 6-diamidino-2-phenylindole medicine.drug_class PBS phosphate-buffered saline PCa prostate cancer HSP90 heat shock protein 90 AKT protein kinase B Cell Line Tumor DAB 3 3′-diaminobezidine LNCaP medicine Humans Metastasis suppressor ADT androgen deprivation therapy NDRG1 N-myc downstream regulated gene 1 Molecular Biology PI3K/AKT/mTOR pathway EGF epidermal growth factor NDRG1 Co-IP coimmunoprecipitation Tumor Suppressor Proteins Prostatic Neoplasms Cell Biology medicine.disease Androgen EGFR epidermal growth factor receptor Tyk2 tyrosine kinase 2 Androgen receptor Cancer research biology.protein AR androgen receptor FCS fetal calf serum EMT epithelial-to-mesenchymal transition MAPK mitogen-activated protein kinase |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | N-myc-downregulated gene 1 (NDRG1) has potent anti-cancer 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. |
| Databáze: | OpenAIRE |
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