title: Benzyl Isothiocyanate (BITC) Induces Reactive Oxygen Species-dependent Repression of STAT3 Protein by Down-regulation of Specificity Proteins in Pancreatic Cancer.
abstract: The antineoplastic agent benzyl isothiocyanate (BITC) acts by targeting multiple pro-oncogenic pathways/genes, including signal transducer and activator of transcription 3 (STAT3); however, the mechanism of action is not well known. As reported previously, BITC induced reactive oxygen species (ROS) in Panc1, MiaPaCa2, and L3.6pL pancreatic cancer cells. This was accompanied by induction of apoptosis and inhibition of cell growth and migration, and these responses were attenuated in cells cotreated with BITC plus glutathione (GSH). BITC also decreased expression of specificity proteins (Sp) Sp1, Sp3, and Sp4 transcription factors (TFs) and several pro-oncogenic Sp-regulated genes, including STAT3 and phospho-STAT3 (pSTAT3), and GSH attenuated these responses. Knockdown of Sp TFs by RNA interference also decreased STAT3/pSTAT3 expression. BITC-induced ROS activated a cascade of events that included down-regulation of c-Myc, and it was also demonstrated that c-Myc knockdown decreased expression of Sp TFs and STAT3 These results demonstrate that in pancreatic cancer cells, STAT3 is an Sp-regulated gene that can be targeted by BITC and other ROS inducers, thereby identifying a novel therapeutic approach for targeting STAT3.
authors.affiliation: From the Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466.
authors.forename: Ravi
authors.initials: R
authors.lastname: Kasiappan
authors.affiliation: From the Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466.
authors.forename: Indira
authors.initials: I
authors.lastname: Jutooru
authors.affiliation: From the Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466.
authors.forename: Keshav
authors.initials: K
authors.lastname: Karki
authors.affiliation: From the Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466.
authors.forename: Erik
authors.initials: E
authors.lastname: Hedrick
authors.affiliation: From the Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466 ssafe@cvm.tamu.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D051703:Sp Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D017879:Isothiocyanates; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051703:Sp Transcription Factors; C031403:benzyl isothiocyanate
keywords: Myc (c-Myc); STAT3; pancreatic cancer; reactive oxygen species (ROS); specificity protein 1 (Sp1)