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/b-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 b-catenin or b-catenin shRNA, suggesting it does not involve Wnt/b-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 þ 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 b-cateninindependent Wnt signalling in the control of AR activity and provide one explanation for sFRP1 downregulation in prostate cancer.

WNT Signaling in Prostate Development and Carcinogenesis

“…SFRP1 was reported as downregulated both in prostate cancer and cell lines 88 . Kawano et al 77 found SFRP1 as a negative regulator of the androgen receptor but this was mediated via neither canonical nor known non-canonical Wnt pathways. A physical interaction of SFRP1 with Frizzled receptors was found and a novel, so far uncharacterized pathway which might be shared with Wnt5a, has been suggested 77,89 .…”

“…Kawano et al 77 found SFRP1 as a negative regulator of the androgen receptor but this was mediated via neither canonical nor known non-canonical Wnt pathways. A physical interaction of SFRP1 with Frizzled receptors was found and a novel, so far uncharacterized pathway which might be shared with Wnt5a, has been suggested 77,89 . The role of SFRP1 may depend both on cell and receptor specific context as Joesting et al 90 reported elevated expression of SFRP1 in fibroblasts derived from prostate cancer stroma.…”

“…Briefly, AR activity may be affected by GSK-3β kinase activity 74,75 and the AR gene is also a direct target of LEF-1/TCF transcriptional regulation 76 . Wnt inhibitor SFRP1 has recently been reported as a negative regulator of androgen receptor activity 77 (also see below). Interestingly, Wn t signaling is upregulated following castration but downregulated after androgen replacement 47,78 .…”

Coregulation of srGAP1 by Wnt and Androgen Receptor Signaling: A New Target for Treatment of CRPC

“…SFRP1 can function as a negative regulator of the AR [120]. However, this effect of sFRP1 was not associated with Wnt inhibition [120]. Joesting et al [121] found that sFRP1 was overexpressed in prostate cancer stromal cells and ovexpression of sFRP1 activated JNK pathway, but not the canonical Wnt pathway.…”

“…The sFRP family member sFRP1 was also found to be down-regulated both in prostate cancer tissues and prostate cancer cell lines. SFRP1 can function as a negative regulator of the AR [120]. However, this effect of sFRP1 was not associated with Wnt inhibition [120].…”