Pancreatic cancer-specific cell death induced in vivo by cytoplasmic-delivered polyinosine-polycytidylic acid
Authors: Luni Emdad
Qin Gui
Devanand Sarkar
Paul B Fisher
Steven R Grossman
Praveen Bhoopathi
Swadesh K Das
Bridget A Quinn
Xue-Ning Shen
Journal: Cancer Research (2014)
Discipline: CLINICAL MEDICINE
Keywords: pIC; polyethylenimine; apoptosis; pancreatic ductal adenocarcinoma; XIAP
Affiliations: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia., Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. Department of Internal Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia., 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., Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia., Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.  .

Abstract:  Polyinosine-polycytidylic acid [pIC] is a synthetic dsRNA that acts as an immune agonist of TLR3 and RLR to activate dendritic and natural killer cells that can kill tumor cells. pIC can also trigger apoptosis in pancreatic ductal adenocarcinoma cells (PDAC) but its mechanism of action is obscure. In this study, we investigated the potential therapeutic activity of a formulation of pIC with polyethylenimine ([pIC](PEI)) in PDAC and investigated its mechanism of action. [pIC](PEI) stimulated apoptosis in PDAC cells without affecting normal pancreatic epithelial cells. Mechanistically, [pIC](PEI) repressed XIAP and survivin expression and activated an immune response by inducing MDA-5, RIG-I, and NOXA. Phosphorylation of AKT was inhibited by [pIC](PEI) in PDAC, and this event was critical for stimulating apoptosis through XIAP and survivin degradation. In vivo administration of [pIC](PEI) inhibited tumor growth via AKT-mediated XIAP degradation in both subcutaneous and quasi-orthotopic models of PDAC. Taken together, these results offer a preclinical proof-of-concept for the evaluation of [pIC](PEI) as an immunochemotherapy to treat pancreatic cancer. 

Retracted: No

PubPeer comments:
 Fig 6D Bands pasted in pAKT blot ![file] , 
 Also in 6D, splice in right actin ![file] , 
 Fig 5C, more bands pasted in. ![file] , 
 Fig 5C, more bands pasted in ![file] , 
 #2 The band spliced into lane 10 has very similar features and background features to lane 2. ,