CD147 modulates androgen receptor activity through the Akt/Gsk-3β/β-catenin/AR pathway in prostate cancer cells

Abstract

Abstract. The androgen signaling pathway serves an important role in the development of prostate cancer. β-Catenin is an androgen receptor (AR) cofactor and augments AR signaling. Glycogen synthase kinase-3β (GSK-3β), a target of phosphorylated serine/threonine protein kinase B (p-Akt), regulates β-catenin stability. In addition, β-catenin, a coregulator of AR, physically interacts with AR and enhances AR-mediated target gene transcription. The multifunctional glycoprotein cluster of differentiation (CD) 147 is highly expressed on the cell surface of the majority of cancer cells, and it promotes tumor invasion, metastasis and growth. In the present study, the molecular effects of CD147 on the Akt/GSK-3β/β-catenin/AR signaling network were investigated in LNCaP cells. Using short hairpin-mediated RNA knockdown of CD147 in LNCaP cells, it was demonstrated that downregulation of CD147 resulted in inhibitory phosphorylation of GSK-3β, and then promoted degeneration of β-catenin and reduced nuclear accumulation of β-catenin. In addition, immunoprecipitation studies demonstrated that CD147 downregulation decreased the formation of a complex between β-catenin and AR. It was shown that CD147 knockdown suppressed the expression of the AR target gene prostate-specific antigen and the growth of AR-positive LNCaP cells. Furthermore, inhibition of PI3K/Akt with LY294002 augmented CD147-mediated function. The present study indicates that the PI3K/Akt pathway may facilitate CD147-mediated activation of the AR pathway.

CD147 promotes collective invasion through cathepsin B in hepatocellular carcinoma

“…Our previous data showed that overexpression of CD147 promoted β-catenin nuclear translocation in HCC (66)(67)(68). And CD147 was also reported to modulate androgen receptor activity through β-catenin pathway in prostate cancer (69). Together with the data reported here, these results indicate that β-catenin signaling is key downstream pathway which mediates divers tumor promotion effects of CD147.…”

CD147 promotes collective invasion through cathepsin B in hepatocellular carcinoma

“…Our previous data showed that overexpression of CD147 promoted β-catenin nuclear translocation in HCC [ 24 , 58 ]. And CD147 was also reported to modulate androgen receptor activity through β-catenin pathway in prostate cancer [ 59 ]. Together with the data reported here, these results indicate that β-catenin signaling is key downstream pathway which mediates divers tumor promotion effects of CD147.…”

Up-regulation of Biglycan is Associated with Poor Prognosis and PTEN Deletion in Patients with Prostate Cancer

“…Reasons for the tumor-associated up-regulation may include the role of BGN as a downstream target of various growth and signal transduction pathways like TGFb, Wnt and Akt signaling [31] , [32] , [33] , activation of which is frequently found in malignant tumors [34] , [35] , [36] , [37] . The general importance of these pathways in prostate cancer [38] , [39] , [40] , [41] may not only explain the high fraction of BGN expressing cancers but also its comparatively low prognostic impact. That BGN up-regulation has also been linked to reduce cell proliferation in some cell lines from cancers and fibroblasts [12] , [15] , [42] is consistent with the cell-type dependent effects of BGN expression.…”