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PMID:19277043

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Citation

Kawano, Y, Diez, S, Uysal-Onganer, P, Darrington, RS, Waxman, J and Kypta, RM (2009) Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer. Br. J. Cancer 100:1165-74

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.

Links

PubMed PMC2669996 Online version:10.1038/sj.bjc.6604976

Keywords

Cell Line, Tumor; Cell Proliferation; Glycoproteins/physiology; Humans; Male; Prostatic Neoplasms/metabolism; Prostatic Neoplasms/pathology; Proto-Oncogene Proteins/physiology; Receptors, Androgen/genetics; Repressor Proteins/physiology; Signal Transduction; Wnt Proteins/physiology; beta Catenin/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SFRP1

involved_in

GO:0008285: negative regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

enables

GO:0005109: frizzled binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9ULV1

F

Seeded From UniProt

complete

HUMAN:SFRP1

enables

GO:0005109: frizzled binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9NPG1

F

Seeded From UniProt

complete

HUMAN:SFRP1

enables

GO:0005109: frizzled binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UP38

F

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0060766: negative regulation of androgen receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FZD3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8N474

F

Seeded From UniProt

complete

HUMAN:FZD4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8N474

F

Seeded From UniProt

complete

HUMAN:FZD1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8N474

F

Seeded From UniProt

complete

HUMAN:WNT5A

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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