Loss of PTEN Permits CXCR4-Mediated Tumorigenesis through ERK1/2 in Prostate Cancer Cells

被引:45
作者
Chetram, Mahandranauth A. [1 ]
Odero-Marah, Valerie [1 ,2 ]
Hinton, Cimona V. [1 ]
机构
[1] Clark Atlanta Univ, Ctr Canc Res & Therapeut Dev, Atlanta, GA 30314 USA
[2] Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA
基金
美国国家卫生研究院;
关键词
LIPID PHOSPHATASE-ACTIVITY; CHEMOKINE RECEPTOR CXCR4; TUMOR-SUPPRESSOR GENE; SIGNALING PATHWAY; BONE MICROENVIRONMENT; EXPRESSION; METASTASIS; MIGRATION; GROWTH; INACTIVATION;
D O I
10.1158/1541-7786.MCR-10-0235
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
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 PTEN may permit CXCR4 to progress prostate cancer to an advanced disease. In the present study, we investigated the involvement of PTEN in CXCR4-mediated 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 PTEN-expressing 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. (C) 2010 AACR.
引用
收藏
页码:90 / 102
页数:13
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