Pancreatic Cancer–Specific Cell Death Induced In Vivo by Cytoplasmic-Delivered Polyinosine–Polycytidylic Acid

Abstract

Polyinosine-polycytidylic acid (pIC) is a synthetic dsRNA that acts as an immune agonist of TLR3 and RLR to activate dendritic and NK cells that can kill tumor cells. pIC can also trigger apoptosis in pancreatic ductal adenocarcinoma cells 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.

Platinum-resistance and AKT Over-expression in Ovarian Cancer

“…Furthermore AKT seems to be able to influence directly the immune resistance of malignant cells e.g. ovarian tumour cells [73,95,[129][130][131]. Comparison of parental and immuneresistant ovarian tumours revealed that AKT is highly activated in the immune-resistant tumours.…”

“…Conversely, there is accumulating evidence that the PI3K/AKT/mTOR pathway is involved in the development of several malignant traits of cancer cells as well as their escape from immunity [128]. In some studies the interactions between cancer cells and natural-killer (NK)-cells have been enlightened [73,95,[129][130][131]. Modified FATAL assay was used for determining the killing efficiency of NK-cells in regard to ovarian cancer cell models in-vitro.…”

The Quest for an Effective Treatment for an Intractable Cancer

“…Adapted from Quinn et al (2015). (Ammi et al, 2015;Bhoopathi et al, 2014). TLRs act as primary sensors, recognizing innate patterns of bacterial or viral infection (Barral et al, 2009).…”

“…Through these pathways, pIC can directly activate dendritic cells and promote NK cells to attack tumors by mimicking viral RNA (Perrot et al, 2010). While pIC has been utilized extensively in clinical trials (Gnjatic, Sawhney, & Bhardwaj, 2010), only recently has the mechanism of action in pancreatic cells been uncovered (Bhoopathi et al, 2014). pIC exposure induces elevated levels of proteins involved in viral and tumoral host defenses, including type I IFNs, OAS, RIG-I helicase, and MDA-5 (Barral et al, 2009;Gnjatic et al, 2010).…”

“…Recent experiments in pancreatic cancer showed that [pIC] PEI repressed XIAP and survivin expression, as well as promoting an immune response through induction of MDA-5, RIG-I, and NOXA. Furthermore, Akt activation was inhibited by [pIC] PEI in pancreatic cancer cells, proving to be a crucial step in apoptosis through XIAP and survivin degradation (Bhoopathi et al, 2014).…”