ADAM17 regulates prostate cancer cell proliferation through mediating cell cycle progression by EGFR/PI3K/AKT pathway
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A disintegrin and metalloprotease 17 (ADAM17) is a transmembrane protein that can cleave membrane anchored proteins to release soluble factors and regulate important biological phenomena in cancers. In the present study, we evaluated the effects of ADAM17 on the proliferation and on the cell cycle distribution of human prostate cancer cells. Experiments were also performed to gain insights into the possible mechanism of action of ADAM17. We used over-expression and RNAi strategy to investigate the function of ADAM17 in human prostate cancer cells. Changes in rate of proliferation and cell cycle profile were measured by growth curve, Cell Counting Kit-8 (CCK-8) assay, bromodeoxyuridine (BrdU) incorporation assay and cell cycle analysis. In addition, changes in expression of associated genes and proteins were studied by semiquantitative RT-PCR, western blotting and ELISA analysis. Ectopic over-expression of ADAM17 resulted in increased cell proliferation. We also showed that ADAM17 promoted G1 to S phase transition concomitantly with upregulation of cyclin E, CDK2 and downregulation of p21 and p27 proteins. ADAM17 over-expression cells showed that more TGF-α released to the supernatant and activated the EGFR/PI3K/AKT pathway. Conversely, silencing ADAM17 led to the opposite effect. Both siRNAs knockdown of ADAM17 and blocking the EGFR/PI3K/AKT pathway using specific inhibitor caused downregulation of cyclin E, CDK2, and upregulation of p21 and p27 in prostate cancer cells. Collectively, this study demonstrates that over-expression of ADAM17 might target cyclin E, CDK2, p21, and p27 to promote prostate cancer cell proliferation through activation of the EGFR/PI3K/AKT pathway.
KeywordsADAM17 Prostate cancer Cell proliferation Cell cycle EGFR AKT
This research is funded by National Natural Science Foundation of China (No. 30772173), Natural Science Foundation of Heilongjiang Province, China (No. D2007-56) and Innovation Fund for Excellent Graduates of Harbin Medical University (No. HCXS2010001).
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