title: mda-7/IL-24Mediates Cancer Cell-Specific Death via Regulation of miR-221 and the Beclin-1 Axis.
abstract: Melanoma differentiation-associated gene-7/IL-24 (mda-7/IL-24) displays broad-spectrum anticancer activityin vitro, in vivoin preclinical animal models, and in a phase I/II clinical trial in patients with advanced cancers without harming normal cells or tissues. Here we demonstrate thatmda-7/IL-24regulates a specific subset of miRNAs, including cancer-associated miR-221. Either ectopic expression ofmda-7/IL-24or treatment with recombinant His-MDA-7 protein resulted in downregulation of miR-221 and upregulation of p27 and PUMA in a panel of cancer cells, culminating in cell death.Mda-7/IL-24-induced cancer cell death was dependent on reactive oxygen species induction and was rescued by overexpression of miR-221. Beclin-1 was identified as a new transcriptional target of miR-221, andmda-7/IL-24regulated autophagy through a miR-221/beclin-1 feedback loop. In a human breast cancer xenograft model, miR-221-overexpressing MDA-MB-231 clones were more aggressive and resistant tomda-7/IL-24-mediated cell death than parental clones. This is the first demonstration thatmda-7/IL-24directly regulates miRNA expression in cancer cells and highlights the novelty of themda-7/IL-24-miR-221-beclin-1 loop in mediating cancer cell-specific death.Cancer Res; 77(4); 949-59. ©2016 AACR.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Anjan K
authors.initials: AK
authors.lastname: Pradhan
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Sarmistha
authors.initials: S
authors.lastname: Talukdar
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Praveen
authors.initials: P
authors.lastname: Bhoopathi
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. paul.fisher@vcuhealth.org.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D017209:Apoptosis; D000071186:Beclin-1 / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007378:Interleukins / Q000502:physiology*; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D000099180:Interleukin-24
chemical_list: D000071186:Beclin-1; D007378:Interleukins; D035683:MicroRNAs; D017382:Reactive Oxygen Species; D020123:Sirolimus; D000099180:Interleukin-24; C525709:MIR221, human