ABSTRACT
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) emerges as one of the most-promising experimental cancer therapeutic drugs and is currently being tested in clinical trials. However, both intrinsic and acquired resistance of human cancer cells to TRAIL-induced apoptosis poses a huge problem in establishing clinically efficient TRAIL therapies. To assess the regulation of TRAIL-resistance in human pancreatic cancer cells, we studied the TRAIL resistant pancreatic cell line PANC-1. We show that treatment with PH11, a novel Focal Adhesion Kinase (FAK) inhibitor in association with TRAIL rapidly induces apoptosis in TRAIL-resistant PANC-1 cells, but not in normal human fibroblast cells. To explain sensitization, we showed that PH11 restores TRAIL apoptotic pathway in PANC-1 cells through down-regulation of c-FLIP via inhibition of FAK and the phosphatidylinositol-3 kinase (PI3K)/AKT pathways. These findings suggest that this combined treatment may offer an attractive therapeutic strategy for safely and efficiently treating pancreatic cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Drug Resistance, Neoplasm/drug effects , Focal Adhesion Kinase 1/antagonists & inhibitors , Imidazoles/pharmacology , Pancreatic Neoplasms/enzymology , Pancreatic Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Triazines/pharmacology , CASP8 and FADD-Like Apoptosis Regulating Protein/genetics , CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism , Caspases/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Enzyme Activation , Focal Adhesion Kinase 1/genetics , Focal Adhesion Kinase 1/metabolism , Humans , Molecular Targeted Therapy , Pancreatic Neoplasms/genetics , Phosphatidylinositol 3-Kinase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , Signal Transduction/drug effects , Time Factors , TransfectionABSTRACT
HIV elite controllers (EC) are a rare group of HIV-infected patients who are able to maintain undetectable viral loads during a long period of time in the absence of antiretroviral treatment. Adaptive immunity and host genetic factors, although implicated, do not entirely explain this phenomenon. On the other hand, plasmacytoid dendritic cells (pDCs) are the principal type I interferon (IFN) producers in response to viral infection, and it is unknown whether pDCs are involved in the control of HIV infection in EC. In our study, we analyzed peripheral pDC levels and IFN-α production by peripheral blood mononuclear cells (PBMCs) in EC compared to other groups of HIV-infected patients, the ability of pDCs to reduce HIV production in vitro, and the mechanisms potentially involved. We showed preserved pDC counts and IFN-α production in EC. We also observed a higher capacity of pDCs from EC to reduce HIV production and to induce T cell apoptosis, whereas pDCs from viremic patients barely responded without previous Toll-like receptor 9 (TLR-9) stimulus. The preserved functionality of pDCs from EC to reduce viral production may be one of the mechanisms involved in the control of HIV viremia in these subjects. These results demonstrate the importance of innate immunity in HIV pathogenesis, and an understanding of pDC mechanisms would be helpful for the design of new therapies.
