ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to             promote prostate cancer cell invasion.
ADAM17, also known as tumor necrosis factor-α converting enzyme (TACE),             is involved in proteolytic ectodomain shedding of cell surface molecules and cytokines.             Although aberrant expression of ADAM17 has been shown in various malignancies,             the function of ADAM17 in prostate cancer has not been clarified. In the present             study, we sought to elucidate whether ADAM17 contributes to prostate cancer cell             invasion, as well as the mechanism involved in the process. The expression pattern             of ADAM17 was investigated in human prostate cancer cells. The results showed             that ADAM17 expression levels are correlated with the invasive ability of androgen-independent             prostate cancer cell lines. Further, ADAM17 was overexpressed in cells showing             high invasion characteristics, activation of the EGFR-MEK-ERK pathway, up-regulation             of MMP-2, MMP-9, and an increased TGF-α release into the supernatant. However,             AG1478, PD98059 and antibody against TGF-α deactivating the EGFR-MEK-ERK signaling             pathway, abolished up-regulation of MMP-2, MMP-9 and prevented cell invasion.             In addition, cells with knockdown of ADAM17 by siRNA exhibited low invasive ability,             deactivated EGFR-MEK-ERK signaling pathway, reduced TGF-α released and down-regulation             of MMP-2, MMP-9. However, these effects could be reversed by simultaneous addition             of TGF-α. These data demonstrated that ADAM17 contributes to androgen-independent             prostate cancer cell invasion by shedding of EGFR ligand TGF-α, which subsequently             activates the EGFR-MEK-ERK signaling pathway, leading finally to overexpression             of MMP-2 and MMP-9. This study suggests that the ADAM17 expression level may be             a new predictive biomarker of invasion and metastasis of prostate cancer, and             ADAM17 could provide a target for treating metastatic PCa.
Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Harbin Medical University, 194 Xuefu Road, Harbin 150081, Heilongjiang, PR China.
Li-Jie
LJ
Xiao
Ping
P
Lin
Feng
F
Lin
Xin
X
Liu
Wei
W
Qin
Hai-Feng
HF
Zou
Liang
L
Guo
Wei
W
Liu
Shu-Juan
SJ
Wang
Xiao-Guang
XG
Yu
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D045744:Cell Line, Tumor; D002465:Cell Movement; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D015854:Up-Regulation
D047428:Protein Kinase Inhibitors; D016211:Transforming Growth Factor alpha; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D051722:ADAM Proteins; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human