title: Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer.
abstract: Secreted Frizzled-related protein-1 (sFRP1) associates with Wnt proteins and its loss can lead to activation of Wnt/beta-catenin signalling. It is frequently downregulated in cancer, including prostate cancer, but its function in prostate cancer is unclear because it can increase proliferation of prostate epithelial cells. We investigated the function of sFRP1 in androgen-dependent prostate cancer and found that sFRP1 inhibited androgen receptor (AR) transcriptional activity. In addition, sFRP1 inhibited the proliferation of androgen-dependent LNCaP cells but not of an androgen-independent subline LNCaP-r, suggesting a role in androgen-dependent growth. The inhibition of AR by sFRP1 was unaffected by co-expression of Wnt3a, stabilised beta-catenin or beta-catenin shRNA, suggesting it does not involve Wnt/beta-catenin signalling. Wnt5a also inhibited AR and expression of Wnt5a and sFRP1 together did not further inhibit AR, suggesting that Wnt5a and sFRP1 activate the same signal(s) to inhibit AR. However, sFRP1 inhibition of AR was unaffected by inhibitors of kinases involved in Wnt/Ca(2+) and Wnt/planar cell polarity non-canonical Wnt signalling. Interestingly, the cysteine-rich domain of sFRP1 interacted with Frizzled receptors expressed in prostate cancer cells, suggesting that sFRP1/Frizzled complexes activate a signal that leads to repression of AR. Taken together, these observations highlight the function of beta-catenin-independent Wnt signalling in the control of AR activity and provide one explanation for sFRP1 downregulation in prostate cancer.
authors.affiliation: Prostate Cancer Research Group, Department of Oncology, Imperial College London, London, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawano
authors.forename: S
authors.initials: S
authors.lastname: Diez
authors.forename: P
authors.initials: P
authors.lastname: Uysal-Onganer
authors.forename: R S
authors.initials: RS
authors.lastname: Darrington
authors.forename: J
authors.initials: J
authors.lastname: Waxman
authors.forename: R M
authors.initials: RM
authors.lastname: Kypta
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D011944:Receptors, Androgen / Q000235:genetics*; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000502:physiology; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000502:physiology; D000099274:Frizzled-Related Proteins
chemical_list: D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D012097:Repressor Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; C410798:AR protein, human; C495270:CTNNB1 protein, human; C085389:WNT5A protein, human