title: Autophagy plays a critical role in ChLym-1-induced cytotoxicity of non-hodgkin's lymphoma cells.
abstract: Autophagy is a critical mechanism in both cancer therapy resistance and tumor suppression. Monoclonal antibodies have been documented to kill tumor cells via apoptosis, antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In this study, we report for the first time that chLym-1, a chimeric anti-human HLA-DR monoclonal antibody, induces autophagy in Raji Non-Hodgkin's Lymphoma (NHL) cells. Interestingly, inhibition of autophagy by pharmacological inhibitors (3-methyladenine and NH4Cl) or genetic approaches (siRNA targeting Atg5) suppresses chLym-1-induced growth inhibition, apoptosis, ADCC and CDC in Raji cells, while induction of autophagy could accelerate cytotoxic effects of chLym-1 on Raji cells. Furthermore, chLym-1-induced autophagy can mediate apoptosis through Caspase 9 activation, demonstrating the tumor-suppressing role of autophagy in antilymphoma effects of chLym-1. Moreover, chLym-1 can activate several upstream signaling pathways of autophagy including Akt/mTOR and extracellular signal-regulated kinase 1/2 (Erk1/2). These results elucidate the critical role of autophagy in cytotoxicity of chLym-1 antibody and suggest a potential therapeutic strategy of NHL therapy by monoclonal antibody chLym-1 in combination with autophagy inducer.
authors.affiliation: Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Fan
authors.forename: Xian
authors.initials: X
authors.lastname: Zeng
authors.forename: Yubin
authors.initials: Y
authors.lastname: Li
authors.forename: Shaofei
authors.initials: S
authors.lastname: Wang
authors.forename: Ziyu
authors.initials: Z
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Sun
authors.forename: Hongjian
authors.initials: H
authors.lastname: Gao
authors.forename: Guoping
authors.initials: G
authors.lastname: Zhang
authors.forename: Meiqing
authors.initials: M
authors.lastname: Feng
authors.forename: Dianwen
authors.initials: D
authors.lastname: Ju
mesh_terms: D000643:Ammonium Chloride / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008228:Lymphoma, Non-Hodgkin; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D000643:Ammonium Chloride; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020123:Sirolimus