title: BAY61-3606 potentiates the anti-tumor effects of TRAIL against colon cancer through up-regulating DR4 and down-regulating NF-κB.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is well known for its ability to preferentially induce apoptosis in malignant cells without causing damage to most normal cells. However, inherent and acquired resistance of tumor to TRAIL-induced apoptosis limits its therapeutic applicability. Here we show that the orally available tyrosine kinase inhibitor, BAY61-3606, enhances the sensitivity of human colon cancer cells, especially those harboring active mutations in Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene, to TRAIL-induced apoptosis in vitro and in vivo. The sensitization was achieved by up-regulating death receptor 4 (DR4) and the tumor suppressor p53. BAY61-3606-induced the up-regulation of DR4 is p53-dependent. Knockout of p53 decreased BAY61-3606-induced DR4 expression and inhibited the effect of BAY61-3606 on TRAIL-induced apoptosis. In addition, BAY61-3606 suppressed activity of NF-κB and regulated its gene products, which might also contribute to TRAIL-induced apoptosis. In conclusion, our results showed that BAY61-3606 sensitizes colon cancer cells to TRAIL-induced apoptosis via up-regulating DR4 expression in p53-dependent manner and inhibiting NF-κB activity, suggesting that the combination of TRAIL and BAY61-3606 may be a promising therapeutic approach in the treatment of colon cancer.
authors.affiliation: West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: dujipei2007@126.com.
authors.forename: Jipei
authors.initials: J
authors.lastname: Du
authors.affiliation: West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: wangyufang@scu.edu.cn.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, China; Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, 100000, China. Electronic address: degaochen@sina.com.
authors.forename: Degao
authors.initials: D
authors.lastname: Chen
authors.affiliation: West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: jiguangyu4601@163.com.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Ji
authors.affiliation: West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: mqz2080@163.com.
authors.forename: Qizhao
authors.initials: Q
authors.lastname: Ma
authors.affiliation: West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: Liaoshiping@163.com.
authors.forename: Shiping
authors.initials: S
authors.lastname: Liao
authors.affiliation: West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: Zhengyj@163.com.
authors.forename: Yanjiang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: zhangj@scu.edu.cn.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.affiliation: West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: forensic@scu.edu.cn.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Hou
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: C477642:2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide; D051017:Apoptosis Regulatory Proteins; C117307:KRAS protein, human; D016328:NF-kappa B; D011743:Pyrimidines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D009536:Niacinamide; D016283:Proto-Oncogene Proteins p21(ras)
keywords: BAY61-3606; Death receptor 4; NF-κB; TRAIL; p53