title: Retinoid- and sodium-butyrate-induced decrease in heat shock protein 70 membrane-positive tumor cells is associated with reduced sensitivity to natural killer cell lysis, growth delay, and altered growth morphology.
abstract: Human tumors frequently present heat shock protein 70 (Hsp70) on their cell membranes, whereas corresponding normal tissues fail to do so. Therefore, an Hsp70 membrane-positive phenotype provided a tumor-specific marker. Moreover, membrane-bound Hsp70 provides a target structure for the cytolytic attack mediated by natural killer (NK) cells. Vitamin A derivatives 13-cis retinoic acid (13-RA) and all-trans retinoic acid (ATRA) and sodium-butyrate (SBU) are known for their redifferentiating capacity. Therefore, we asked the question whether loss in tumorigenicity might be associated with a reduced Hsp70 membrane expression. For our studies we used epithelial colon (CX+/CX-) and thyroid (ML-1) cancer cells, with initially different Hsp70 cell surface expression pattern. After treatment up to 7 weeks with freshly prepared 13-RA, ATRA, and SBU at nonlethal concentrations of 10 microM, 1 microM, and 0.5 mM, respectively, growth morphology, Hsp70 levels, and sensitivity toward Hsp70-specific NK cells were compared with that of untreated tumor cells. Significant growth delay was determined in CX+ tumor cells after 6 weeks treatment with 13-RA. Concomitantly, growth morphology changed from spheroid cell clusters to monolayers. Despite a weak increase in cytosolic Hsp70, the percentage of Hsp70 membrane-positive cells dropped significantly after repeated treatments with 13-RA and ATRA in CX+ and ML-1 but not in CX- tumor cells. Similar results were observed with SBU. Functionally, the decrease in Hsp70 membrane-positive CX+ and ML-1 cells correlated with a reduced sensitivity to lysis mediated by NK cells. In summary, redifferentiating agents predominantly affected Hsp70 membrane-positive tumors. The decrease in Hsp70 membrane positivity correlated with a lower sensitivity to NK lysis, growth delay, and altered growth morphology.
authors.affiliation: Department of Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Gehrmann
authors.forename: Johann
authors.initials: J
authors.lastname: Schönberger
authors.forename: Tanja
authors.initials: T
authors.lastname: Zilch
authors.forename: Lydia
authors.initials: L
authors.lastname: Rossbacher
authors.forename: Gerald
authors.initials: G
authors.lastname: Thonigs
authors.forename: Christoph
authors.initials: C
authors.lastname: Eilles
authors.forename: Gabriele
authors.initials: G
authors.lastname: Multhoff
mesh_terms: D002087:Butyrates / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy* / Q000276:immunology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D005434:Flow Cytometry; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D012176:Retinoids / Q000494:pharmacology*
chemical_list: D002087:Butyrates; D018840:HSP70 Heat-Shock Proteins; D012176:Retinoids