title: Mechanism of action of phenethylisothiocyanate and other reactive oxygen species-inducing anticancer agents.
abstract: Reactive oxygen species (ROS)-inducing anticancer agents such as phenethylisothiocyanate (PEITC) activate stress pathways for killing cancer cells. Here we demonstrate that PEITC-induced ROS decreased expression of microRNA 27a (miR-27a)/miR-20a:miR-17-5p and induced miR-regulated ZBTB10/ZBTB4 and ZBTB34 transcriptional repressors, which, in turn, downregulate specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells. Decreased expression of miR-27a/miR-20a:miR-17-5p by PEITC-induced ROS is a key step in triggering the miR-ZBTB Sp cascade leading to downregulation of Sp TFs, and this is due to ROS-dependent epigenetic effects associated with genome-wide shifts in repressor complexes, resulting in decreased expression of Myc and the Myc-regulated miRs. Knockdown of Sp1 alone by RNA interference also induced apoptosis and decreased pancreatic cancer cell growth and invasion, indicating that downregulation of Sp transcription factors is an important common mechanism of action for PEITC and other ROS-inducing anticancer agents.
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas, USA.
authors.forename: Indira
authors.initials: I
authors.lastname: Jutooru
authors.affiliation: Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas, USA.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Guthrie
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas, USA.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Chadalapaka
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas, USA.
authors.forename: Satya
authors.initials: S
authors.lastname: Pathi
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: KyoungHyun
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Burghardt
authors.affiliation: Institute of Biosciences & Technology, Texas A&M Health Science Center, Houston, Texas, USA.
authors.forename: Un-Ho
authors.initials: UH
authors.lastname: Jin
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas, USA Institute of Biosciences & Technology, Texas A&M Health Science Center, Houston, Texas, USA ssafe@cvm.tamu.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D051705:Sp3 Transcription Factor / Q000096:biosynthesis; D051706:Sp4 Transcription Factor / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; D017879:Isothiocyanates; C524941:MIRN17 microRNA, human; C534451:MIRN20a microRNA, human; C531388:MIRN27 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D051706:Sp4 Transcription Factor; C559929:ZBTB10 protein, human; C516356:ZBTB34 protein, human; C508974:ZBTB4 protein, human; D051705:Sp3 Transcription Factor; C058305:phenethyl isothiocyanate
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