title: Gefitinib enhances human colon cancer cells to TRAIL-induced apoptosis of via autophagy- and JNK-mediated death receptors upregulation.
abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell-specific apoptosis-inducing cytokine with little toxicity to most normal cells. Here, we report that gefitinib and TRAIL in combination produce a potent synergistic effect on TRAIL-sensitive human colon cancer HCT116 cells and an additive effect on TRAIL-resistant HT-29 cells. Interestingly, gefitinib increases the expression of cell surface receptors DR4 and DR5, possibly explaining the synergistic effect. Knockdown of DR4 and DR5 by siRNA significantly decreases gefitinib- and TRAIL-mediated cell apoptosis, supporting this idea. Because the inhibition of gefitinib-induced autophagy by 3-MA significantly decreases DR4 and DR5 upregulation, as well as reduces gefitinib- and TRAIL-induced apoptosis, we conclude that death receptor upregulation is autophagy mediated. Furthermore, our results indicate that death receptor expression may also be regulated by JNK activation, because pre-treatment of cells with JNK inhibitor SP600125 significantly decreases gefitinib-induced death receptor upregulation. Interestingly, SP600125 also inhibits the expression CHOP, yet CHOP has no impact on death receptor expressions. We also find here that phosphorylation of Akt and ERK might also be required for TRAIL sensitization. In summary, our results indicate that gefitinib effectively enhances TRAIL-induced apoptosis, likely via autophagy and JNK- mediated death receptor expression and phosphorylation of Akt and ERK.
authors.affiliation: Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun, 130024, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun, 130024, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun, 130024, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun, 130024, China.
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun, 130024, China.
authors.forename: Guihua
authors.initials: G
authors.lastname: Tai
authors.affiliation: Department of Radiology, The Second Part of the First Hospital, Jilin University, 3302 Jilin Road, Changchun, 130024, China.
authors.forename: Fenglei
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun, 130024, China. chenghr893@nenu.edu.cn.
authors.forename: Hairong
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Jilin Province Key Laboratory on Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun, 130024, China. zhouyf383@nenu.edu.cn.
authors.forename: Yifa
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000077156:Gefitinib; D019073:HT29 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D053218:Receptors, Death Domain / Q000235:genetics* / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D053218:Receptors, Death Domain; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D000077156:Gefitinib
keywords: Autophagy; DR4; DR5; Gefitinib; JNK; TRAIL