Phosphoprotein associated with glycosphingolipid microdomains 1 inhibits             the proliferation and invasion of human prostate cancer cells in vitro through             suppression of Ras activation.
Phosphoprotein associated with glycosphingolipid microdomains 1 (PAG) is             an important negative regulator of immune signaling in T lymphocytes. However,             newly emerging evidence has indicated that PAG may play important roles in tumor             cells. Our previously reported cDNA microarray experiments identified PAG as a             gene down-regulated in the high metastatic potential prostate cancer cell line             PC-3M-1E8. In this study, we investigated the role of PAG in the proliferation,             invasion and metastasis of prostate cancer cells and the underlying mechanisms.             We confirmed that the expression of PAG at both the mRNA and protein levels was             low in PC-3M-1E8 and DU145 cells compared to low metastatic potential prostate             cancer cells PC-3M-2B4. In addition, we demonstrated that the reintroduction of             PAG to PC-3M-1E8 and DU145 cells led to reduced proliferation through cell cycle             arrest, decreased anchorage-independent growth and reduced invasion ability of             tumor cells in vitro. This is the first report demonstrating that PAG inhibits             the proliferation and invasion potential of prostate cancer cells via the interaction             with RasGAP to recruit RasGAP to the cell membrane, where RasGAP hydrolyzes GTP             to GDP, reduces the level of activated Ras, and ultimately suppresses the activation             of ERK1/2, cyclin D1 and other effectors of the Ras signaling pathway. Morphologically,             we observed that PAG could diminish the formation of pseudopodia on the cell surface             and redistribute the intracellular F-actin in PC-3M-1E8 cells, which directly             leads to the decreased invasion and metastasis potential of tumor cells. Taken             together, these results suggest that PAG acts to inhibit the development and metastasis             of prostate cancers and represents a novel therapeutic target for prostate cancer.
Department of Pathology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, PR China.
Wenjuan
W
Yu
Yuewei
Y
Wang
Miaozi
M
Gong
Fei
F
Pei
Jie
J
Zheng
D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D006028:Glycosphingolipids / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism*
D006028:Glycosphingolipids; D018631:ras Proteins