title: Regulation of STAT3 and NF-κB activations by S-nitrosylation in multiple myeloma.
abstract: Numerous reports suggest that aberrant activations of STAT3 and NF-κB promote survival and proliferation of multiple myeloma (MM) cells. In the present report, we demonstrate that a synthetic S-nitrosothiol compound, S-nitroso-N-acetylcysteine (SNAC), inhibits proliferation and survival of multiple MM cells via S-nitrosylation-dependent inhibition of STAT3 and NF-κB. In human MM cells (e.g. U266, H929, and IM-9 cells), SNAC treatment increased S-nitrosylation of STAT3 and NF-κB and inhibited their activities. Consequently, SNAC treatment resulted in MM cell cycle arrest at G1/S check point and inhibited their proliferation. SNAC also decreased the expression of cell survival factors and increased the activities of caspases, thus increased sensitivity of MM cells to melphalan, a chemotherapeutic agent for MM. In U266 xenografted mice, SNAC treatment decreased the activity of STAT3 and reduced the growth of human CD138 positive cells (U266 cells) in the bone marrow and also reduced their production of human IgE into the serum. Taken together, these data document the S-nitrosylation mediated inhibition of MM cell proliferation and cell survival via inhibition of STAT3 and NF-κB pathways and its efficacy in animal model of MM.
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Jinsu
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Seungho
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Nishant
authors.initials: N
authors.lastname: Saxena
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, United States; Pathology and Laboratory Medicine Service, Ralph H. Johnson Veterans Administration Medical Center, Charleston, SC 29401, United States.
authors.forename: Avtar K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, United States. Electronic address: singhi@musc.edu.
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, United States. Electronic address: wonj@musc.edu.
authors.forename: Je-Seong
authors.initials: JS
authors.lastname: Won
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C024940:S-nitroso-N-acetylcysteine; D000111:Acetylcysteine
keywords: Apoptosis; Bcl-2; Cdk; Cyclin; Multiple myeloma; NF-κB; Proliferation; S-nitroso-N-acetylcysteine (SNAC); S-nitrosylation; STAT3; U266; Xenograft