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Cisplatin enhances NK cells immunotherapy efficacy to suppress HCC progression via altering the androgen receptor (AR)-ULBP2 signals.
- Source :
-
Cancer letters [Cancer Lett] 2016 Apr 01; Vol. 373 (1), pp. 45-56. Date of Electronic Publication: 2016 Jan 19. - Publication Year :
- 2016
-
Abstract
- The aim of this study is to investigate the influence of cisplatin on the efficacy of natural killer (NK) cells immunotherapy to suppress HCC progression, and provide valuable information on better application of cisplatin in clinical settings. By using in vitro cell cytotoxicity test and in vivo liver orthotopic xenograft mice model, we identified the role of cisplatin in modulating NK cells cytotoxicity. Luciferase report assay and chromatin immunoprecipitation assay were applied for mechanism dissection. Immunohistochemistry is performed for sample staining. We found cisplatin could enhance the efficacy of NK cells immunotherapy to better suppress HCC progression via altering the androgen receptor (AR)-UL16-binding protein 2 (ULBP2) signals both in vitro and in vivo. Mechanism dissection revealed that cisplatin could suppress AR expression via two distinct ways: increasing miR-34a-5p to suppress AR expression and altering the ubiquitination to accelerate the AR protein degradation. The suppressed AR might then function through up-regulating ULBP2, a natural-killer group 2 member D ligand, to enhance the cytotoxicity of NK cells. Together, these results indicated an unrecognized favoring effect of cisplatin in HCC treatment. By suppressing AR in HCC, cisplatin could up-regulate cytotoxicity of NK cells to better target HCC. This finding may provide a potential new approach to control HCC by combining traditional chemotherapy with immunotherapy.<br /> (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
- Subjects :
- Animals
Carcinoma, Hepatocellular genetics
Carcinoma, Hepatocellular metabolism
Carcinoma, Hepatocellular pathology
Cell Line, Tumor
Cell Survival drug effects
Cytotoxicity, Immunologic drug effects
Disease Progression
Dose-Response Relationship, Drug
GPI-Linked Proteins genetics
GPI-Linked Proteins metabolism
HEK293 Cells
Humans
Intercellular Signaling Peptides and Proteins genetics
Killer Cells, Natural immunology
Killer Cells, Natural metabolism
Ligands
Liver Neoplasms genetics
Liver Neoplasms metabolism
Liver Neoplasms pathology
Male
Mice, Nude
NK Cell Lectin-Like Receptor Subfamily K metabolism
Protein Binding
Receptors, Androgen genetics
Time Factors
Transfection
Ubiquitination
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Carcinoma, Hepatocellular therapy
Cisplatin pharmacology
Immunotherapy, Adoptive methods
Intercellular Signaling Peptides and Proteins metabolism
Killer Cells, Natural drug effects
Killer Cells, Natural transplantation
Liver Neoplasms therapy
Receptors, Androgen metabolism
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 373
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 26805759
- Full Text :
- https://doi.org/10.1016/j.canlet.2016.01.017