title: Retinoic acid elicits cytostatic, cytotoxic and immunomodulatory effects on uveal melanoma cells.
abstract: The current therapy of uveal melanoma (UM) metastases remains inefficient, which warrants the development of new treatment modalities. For the first time we investigated the effects of retinoic acid (RA) on a panel of UM cell lines and found that RA induces morphological changes compatible with differentiation, suppresses proliferation and causes apoptosis in these cells. RA treatment resulted in an increase of p21, p27 and p53 protein levels and G1 arrest in UM cells, which correlated with significant down-modulation of surface Her2/neu proto-oncogene expression. In addition, RA-treated UM cells exhibited increased sensitivity to both MHC class I-restricted killing by cytotoxic T lymphocytes and NK cell-mediated lysis that were accompanied by more efficient conjugate formation between UM cells and killer lymphocytes. Taken together, our results implicate UM as a new target for treatment with retinoids and suggest that retinoids and T- or NK-cell based immunotherapy can have mutually enhancing effects in UM patients.
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Simona
authors.initials: S
authors.lastname: Vertuani
authors.forename: Eugenia
authors.initials: E
authors.lastname: Dubrovska
authors.forename: Victor
authors.initials: V
authors.lastname: Levitsky
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
authors.forename: Jelena
authors.initials: J
authors.lastname: Levitskaya
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy*; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects / Q000276:immunology; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras) / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014212:Tretinoin / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000276:immunology; D014604:Uveal Neoplasms / Q000188:drug therapy*
chemical_list: C000715470:MAS1 protein, human; D018809:Proliferating Cell Nuclear Antigen; D000090063:Proto-Oncogene Mas; D016159:Tumor Suppressor Protein p53; C413374:p27 antigen; D014212:Tretinoin; D016283:Proto-Oncogene Proteins p21(ras)