title: Urokinase-type plasminogen activator receptor regulates apoptotic sensitivity of colon cancer HCT116 cell line to TRAIL via JNK-p53 pathway.
abstract: The urokinase-type plasminogen activator receptor (uPAR) serves not only as an anchor for urokinase-type plasminogen activator but also participates in intracellular signal transduction events. In this study, we investigated whether uPAR could modulate TRAIL-induced apoptosis in human colon cancer cells HCT116. Using an antisense strategy, we established a stable HCT116 cell line with down-regulated uPAR. The sensitivity to TRAIL-induced apoptosis was evaluated by FACS analysis. Our results show that the inhibition of uPAR could sensitize HCT116 to TRAIL-induced apoptosis. uPAR inhibition changed the expression of mitochondrial apoptotic pathway proteins, including Bcl-2, Bax, Bid and p53, in a pro-apoptotic manner. We also found that the inhibition of uPAR down-regulated the phosphorylation of FAK, ERK and JNK. The inhibition of p53 by RNA interference rescued cells from enhanced apoptosis, thus indicating that p53 is critical for enhancing TRAIL-induced apoptosis. Furthermore, JNK, but not ERK, inhibition involved in the up-regulation of p53. JNK negatively regulated p53 protein level. Overall, our results show that uPAR inhibition can sensitize colon cancer cells HCT116 to TRAIL-induced apoptosis via active p53 and mitochondrial apoptotic pathways that JNK inhibition is involved.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science, Nanjing University, 22 Han Kou Road, Nanjing, 210093, People's Republic of China.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Liu
authors.forename: Fan
authors.initials: F
authors.lastname: Qiu
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Lan
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Ping-Kun
authors.initials: PK
authors.lastname: Zhou
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.forename: Zi-Chun
authors.initials: ZC
authors.lastname: Hua
mesh_terms: D017209:Apoptosis; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D055293:Receptors, Urokinase Plasminogen Activator; D053221:TNF-Related Apoptosis-Inducing Ligand; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D048670:MAP Kinase Kinase 4