Background:

ASC-J9, is antitumor agent. ASC-J9 suppresses castration-resistant prostate cancer growth via degradation of full-length and splice variant androgen receptors targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor.

The androgen receptor (AR) is a type of nuclear receptor that is activated by binding either of the androgenic hormones, testosterone, or dihydrotestosterone in the cytoplasm and then translocating into the nucleus. [1]The binding of an androgen to the androgen receptor(AR) results into a conformational change, in turn, which causes dissociation of HSP, transport from the cytosol into the cell nucleus, and dimerization. The AR dimer binds to a specific sequence of DNA known as HRE which can interact with other proteins in the nucleus, leading to up-regulation or down-regulation of specific gene transcription.[2]

ASC-J9, the AR degradation enhancer, suppressed both macrophage migration and subsequent PCa cell invasion. Additionally, ASC-J9 can regulate pSTAT3-CCL2 signaling using two pathways: an AR-dependent pathway via inhibiting PIAS3 expression and an AR-independent pathway via direct inhibition of the STAT3 phosphorylation/activation through mouse model in vivo with orthotopically injected TRAMP-C1 cells. In conclusion,a new and better therapeutic strategies using ASC-J9 alone or a combinational therapy that simultaneously targets androgens/AR signaling and PIAS3-pSTAT3-CCL2 signaling to better battle PCa growth and metastasis at castration-resistant stage.[3]

参考文献:

1. Lu NZ. et al. "International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors". Pharmacol. Rev. 2006, 58 (4): 782–97.

2. Heemers HV, Tindall DJ. "Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex". Endocr. Rev. 2007, 28 (7): 778–808.

3. Lin TH. et al. “Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling.” Cell Death

Dis. 2013,4:e764