Expression of Frzb/secreted Frizzled-related protein 3, a secreted Wnt antagonist, in human androgen-independent prostate cancer PC-3 cells suppresses tumor growth and cellular invasiveness.
The ability of Frzb/secreted Frizzled-related protein 3 (sFRP3) to inhibit Wnt signaling and the localization of Frzb/sFRP3 on chromosome 2q to a region frequently deleted in cancers have led some investigators to hypothesize that Frzb/sFRP3 is a tumor suppressor gene. Here, we examined the biological effects of Frzb/sFRP3 on an androgen-independent prostate cancer cell model. We showed that expression of Frzb/sFRP3 in PC-3 cells resulted in decreased colony formation in soft agar and a dramatic inhibition of tumor growth in a xenograft mouse model. When cellular morphology was examined, PC-3 cells expressing Frzb/sFRP3 exhibited an increase in cell-cell contact formation accompanied by a pronounced induction of epithelial markers E-cadherin and keratin-8 and down-regulation of mesenchymal markers N-cadherin, fibronectin, and vimentin. This phenomenon suggested a reversal of epithelial-to-mesenchymal transition and a less invasive phenotype. Indeed, further in vitro studies with a Matrigel assay showed that Frzb/sFRP3 decreased the invasive capacity of PC-3 cells. These changes in the biology of PC-3 cells are associated with a decrease in the expression and activities of both matrix metalloproteinase (MMP)-2 and MMP-9 as well as decreases in AKT activation, cytosolic beta-catenin levels, T-cell factor transcription activity, and expression of Slug and Twist. In addition, transfection of PC-3 with a dominant-negative low-density lipoprotein receptor-related protein 5 (DN-LRP5) coreceptor showed similar biological effects as Frzb/sFRP3 transfection. Together, these data suggest that Frzb/sFRP3 and DN-LRP5 exhibit antitumor activity through the reversal of epithelial-to-mesenchymal transition and inhibition of MMP activities in a subset of prostate cancer.
Zi
Xiaolin
X
Department of Urology, University of California, Irvine, Orange, California 92868, USA.
Guo
Yi
Y
Simoneau
Anne R
AR
Hope
Christopher
C
Xie
Jun
J
Holcombe
Randall F
RF
Hoang
Bang H
BH
D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D002417:Cattle; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D007633:Keratins / Q000096:biosynthesis; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D051153:Wnt Proteins / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000096:biosynthesis; D000094742:Secreted Frizzled-Related Proteins
D015820:Cadherins; D007633:Keratins; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D011506:Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D000094742:Secreted Frizzled-Related Proteins; C555482:LRP5 protein, human; C555483:Lrp5 protein, mouse