Signaling and Regulation Loss of PTEN Permits CXCR4-Mediated Tumorigenesis through ERK1/2 in Prostate Cancer Cells
نویسندگان
چکیده
Loss of PTEN is frequently observed in androgen-independent prostate cancer, resulting in the deregulation of metastatic events. SDF1a activation of CXCR4 induces signaling pathways that have been implicated in prostate metastasis and progression to an advanced disease. The pathways of CXCR4 and PTEN converge, leading to the promotion and regulation of tumorigenesis, respectively. However, loss of PTENmay permit CXCR4 to progress prostate cancer to an advanced disease. In the present study, we investigated the involvement of PTEN in CXCR4mediated tumorigenesis. When screening advanced metastatic prostate cancer cell lines for PTEN, we observed a loss of expression in PC3 and LNCaP cells whereas Du145 expressed wild-type PTEN. All three cell lines were positive for surface expression of CXCR4. Reconsitution of PTEN induced a mesenchymal to epithelial like morphologic change and inhibited CXCR4-mediated migration and proliferation in PC3 cells. Downregulation of PTEN by siRNA enhanced the CXCR4-mediated migratory behavior of Du145 cells. By Western blot analysis, we observed that PTEN inhibited basal AKT phosphorylation but not ERK1/2 phosphorylation in PTENexpressing cells. Upon CXCR4 stimulation, PTEN inhibited ERK1/2 phosphorylation but not phosphorylation of AKT. The CXCR4-mediated migration of PC3 cells was through the ERK1/2 pathway, as confirmed by chemical inhibitors. On the basis of these studies, we suggest that loss of PTEN permits CXCR4-mediated functions in prostate cancer cells through the ERK1/2 pathway. Antagonizing CXCR4 and downstream signaling cascades may provide an efficient approach for treating patients with advanced prostate cancer when hormone therapy fails to the stop the growth and containment of tumors. Mol Cancer Res; 9(1); 90–102. 2010 AACR.
منابع مشابه
Loss of PTEN permits CXCR4-mediated tumorigenesis through ERK1/2 in prostate cancer cells.
Loss of PTEN is frequently observed in androgen-independent prostate cancer, resulting in the deregulation of metastatic events. SDF1α activation of CXCR4 induces signaling pathways that have been implicated in prostate metastasis and progression to an advanced disease. The pathways of CXCR4 and PTEN converge, leading to the promotion and regulation of tumorigenesis, respectively. However, loss...
متن کاملSignaling mechanisms coupled to CXCL12/CXCR4-mediated cellular proliferation are PTEN-dependent.
A key difference between normal and malignant prostate cells in vitro and in vivo is that both alleles of PTEN are largely intact in normal benign prostate glands and cultured epithelial cells, whereas one or both alleles of PTEN are mutant or deleted in the majority of prostate tumors and malignant prostate cancer cell lines. Intact PTEN suppresses phosphorylation of Akt downstream of PI3K act...
متن کاملAnti-cancer properties of Escherichia coli Nissle 1917 against HT-29 colon cancer cells through regulation of Bax/Bcl-xL and AKT/PTEN signaling pathways
Objective(s): Chemotherapies used to treat colon cancer might often fail due to the emergence of chemoresistance and side effects. Escherichia coli Nissle 1917 (EcN) is a beneficial probiotic, whose molecular mechanisms in the prevention of colon cancer are yet to be fully understood. The present study assessed the anti-cancer effects of EcN treatments in human colorec...
متن کاملSprouty genes function in suppression of prostate tumorigenesis.
Expression of Sprouty genes is frequently decreased or absent in human prostate cancer, implicating them as suppressors of tumorigenesis. Here we show they function in prostate tumor suppression in the mouse. Concomitant inactivation of Spry1 and Spry2 in prostate epithelium causes ductal hyperplasia and low-grade prostatic intraepithelial neoplasia (PIN). However, when Spry1 and Spry2 loss-of-...
متن کاملResidual prostate cancer cells after docetaxel therapy increase the tumorigenic potential via constitutive signaling of CXCR4, ERK1/2 and c-Myc.
UNLABELLED Despite an increasing prevalence of patients with docetaxel-refractory prostate cancer, little is known about the tumor biology of the docetaxel-resistant residual tumor cells compared with primary tumor cells. In this study, tumorigenic potential was increased in the docetaxel-resistant residual prostate cancer cell lines (DRD, 1G7 and PC3DR) compared with parental cells (DU145 or P...
متن کامل