title: Autocrine TNF-α-mediated NF-κB activation is a determinant for evasion of CD40-induced cytotoxicity in cancer cells.
abstract: Activation of CD40 by CD40L results in diverse effects on different malignant cells, causing either promotion of survival, growth and resistance to chemotherapy, or induction of cytostasis and apoptosis. The molecular mechanisms underlying CD40-mediated growth regulation and apoptosis induction in cancer cell are not fully understood. In this study, we investigated the role of NF-κB activation in CD40-mediated cytotoxicity in cancer cells. The results show that activation of CD40 by recombinant soluble CD40 ligand (rsCD40L) readily induced NF-κB activation and blocking NF-κB significantly enhanced rsCD40L-induced apoptosis in cancer cells. Importantly, autocrine of TNF-α induced by rsCD40L was indispensable for both NF-κB activation and cytotoxicity induction, establishing a dual role of autocrine TNF-α that constitutes both pro-apoptotic and anti-apoptotic arms of CD40 signaling. Our results indicate that autocrine TNF-α-mediated NF-κB activation is a determinant for cancer cells' evasion of CD40L-induced cytotoxicity and blocking NF-κB may have potential for improve the value of CD40 as an anticancer agent.
authors.affiliation: Department of Forensic Analytical Toxicology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, China.
authors.forename: Daoxia
authors.initials: D
authors.lastname: Li
authors.forename: Yingjia
authors.initials: Y
authors.lastname: Zhong
authors.forename: Yuqiong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Xuelian
authors.initials: X
authors.lastname: Zheng
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Youyi
authors.initials: Y
authors.lastname: Yan
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.forename: Linchuan
authors.initials: L
authors.lastname: Liao
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D019898:Autocrine Communication; D016227:Benzoquinones / Q000494:pharmacology; D019013:CD40 Antigens / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D047311:Luteolin / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology*; D019139:Tumor Escape; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D016227:Benzoquinones; D019013:CD40 Antigens; D047029:Lactams, Macrocyclic; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D023201:CD40 Ligand; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D047311:Luteolin
keywords: Autocrine; CD40/rsCD40L; Cancer; Cell death; NF-κB; TNF-α