title: Reversing translational suppression and induction of toxicity in pancreatic cancer cells using a chemoprevention gene therapy approach.
abstract: Pancreatic cancer is an aggressive disease with limited therapeutic options. Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), a potent antitumor cytokine, shows cancer-specific toxicity in a vast array of human cancers, inducing endoplasmic reticulum stress and apoptosis, toxic autophagy, an antitumor immune response, an antiangiogenic effect, and a significant "bystander" anticancer effect that leads to enhanced production of this cytokine through autocrine and paracrine loops. Unfortunately, mda-7/IL-24 application in pancreatic cancer has been restricted because of a "translational block" occurring after Ad.5-mda-7 gene delivery. Our previous research focused on developing approaches to overcome this block and increase the translation of the MDA-7/IL-24 protein, thereby promoting its subsequent toxic effects in pancreatic cancer cells. We demonstrated that inducing reactive oxygen species (ROS) after adenoviral infection of mda-7/IL-24 leads to greater translation into MDA-7/IL-24 protein and results in toxicity in pancreatic cancer cells. In this study we demonstrate that a novel chimeric serotype adenovirus, Ad.5/3-mda-7, displays greater efficacy in delivering mda-7/IL-24 compared with Ad.5-mda-7, although overall translation of the protein still remains low. We additionally show that d-limonene, a dietary monoterpene known to induce ROS, is capable of overcoming the translational block when used in combination with adenoviral gene delivery. This novel combination results in increased polysome association of mda-7/IL-24 mRNA, activation of the preinitiation complex of the translational machinery in pancreatic cancer cells, and culminates in mda-7/IL-24-mediated toxicity.
authors.affiliation: Department of Human and Molecular Genetics (S.S., B.A.Q., X.S., S.K.D., L.E., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (P.D.), VCU Institute of Molecular Medicine (P.D., S.K.D., L.E., D.S., P.B.F.), and VCU Massey Cancer Center (P.D., L.E., D.S. P.B.F.), Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Siddik
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Department of Human and Molecular Genetics (S.S., B.A.Q., X.S., S.K.D., L.E., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (P.D.), VCU Institute of Molecular Medicine (P.D., S.K.D., L.E., D.S., P.B.F.), and VCU Massey Cancer Center (P.D., L.E., D.S. P.B.F.), Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Quinn
authors.affiliation: Department of Human and Molecular Genetics (S.S., B.A.Q., X.S., S.K.D., L.E., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (P.D.), VCU Institute of Molecular Medicine (P.D., S.K.D., L.E., D.S., P.B.F.), and VCU Massey Cancer Center (P.D., L.E., D.S. P.B.F.), Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Xuening
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Human and Molecular Genetics (S.S., B.A.Q., X.S., S.K.D., L.E., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (P.D.), VCU Institute of Molecular Medicine (P.D., S.K.D., L.E., D.S., P.B.F.), and VCU Massey Cancer Center (P.D., L.E., D.S. P.B.F.), Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.affiliation: Department of Human and Molecular Genetics (S.S., B.A.Q., X.S., S.K.D., L.E., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (P.D.), VCU Institute of Molecular Medicine (P.D., S.K.D., L.E., D.S., P.B.F.), and VCU Massey Cancer Center (P.D., L.E., D.S. P.B.F.), 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 (S.S., B.A.Q., X.S., S.K.D., L.E., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (P.D.), VCU Institute of Molecular Medicine (P.D., S.K.D., L.E., D.S., P.B.F.), and VCU Massey Cancer Center (P.D., L.E., D.S. P.B.F.), 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 (S.S., B.A.Q., X.S., S.K.D., L.E., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (P.D.), VCU Institute of Molecular Medicine (P.D., S.K.D., L.E., D.S., P.B.F.), and VCU Massey Cancer Center (P.D., L.E., D.S. P.B.F.), 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 (S.S., B.A.Q., X.S., S.K.D., L.E., D.S., P.B.F.), Department of Biochemistry and Molecular Biology (P.D.), VCU Institute of Molecular Medicine (P.D., S.K.D., L.E., D.S., P.B.F.), and VCU Massey Cancer Center (P.D., L.E., D.S. P.B.F.), Virginia Commonwealth University, School of Medicine, Richmond, Virginia pbfisher@vcu.edu.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D045744:Cell Line, Tumor; D018890:Chemoprevention / Q000379:methods; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007378:Interleukins / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D046188:Protein Modification, Translational / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099180:Interleukin-24
chemical_list: D007378:Interleukins; D017382:Reactive Oxygen Species; D000099180:Interleukin-24