Gehrmann, Mathias and Brunner, Marion and Pfister, Karin and Reichle, Albert and Kremmer, Elisabeth and Multhoff, Gabriele (2004) Differential up-regulation of cytosolic and membrane-bound heat shock protein 70 in tumor cells by anti-inflammatory drugs. CLINICAL CANCER RESEARCH, 10 (10). pp. 3354-3364. ISSN 1078-0432, 1557-3265
Full text not available from this repository. (Request a copy)Abstract
Purpose: Modulation of the heat shock protein (HSP) response affects sensitivity to therapeutic agents in cancer. Here, drugs with anti-inflammatory potential, (cyclooxygenase 1/2 inhibitors) and peroxidase proliferator-activated receptor-gamma agonists were analyzed for their capacity to affect Hsp70 expression in human cancer cells; with a divergent Hsp70 membrane expression pattern. Experimental Design: In dose kinetics, the nonlethal concentration of acetyl-salicyl acid, celecoxib, rofecoxib, and the insulin-sensitizer pioglitazone was identified for the human adenocarcinoma cell line CX-. With the exception of CLX, which was diluted in DMSO, all reagents were dissolved in water. After treatment with the different compounds at nontoxic concentrations for 6 h, followed by a 1-h recovery period, the cytosolic Hsp70 levels were measured in CX-2 and CX- tumor cells by Western blot analysis. Fold increase was calculated in relation to the housekeeping protein tubulin. Membrane-bound Hsp70 was analyzed by flow cytometry using a FITC-labeled Hsp70-specific monoclonal antibody. Untreated cells and cells incubated with equivalent amounts of the diluting agents served as controls. The immunological function was tested in granzyme B apoptosis assays, standard Cr-51 release assays, and antibody blocking studies. Results: Compared with aqua dest, the cytoplasmic amount of Hsp70 was equally enhanced in CX-2 and CX-cells by all compounds. An increase in membrane-bound Hsp70, detected selectively in CX - cells, corresponded to an enhanced sensitivity to granzyme B- and natural killer cell-mediated kill that was blockable by using a Hsp70-specific antibody. Conclusions: Although increase in cytosolic Hsp70 levels conferred resistance to further stress, membrane-bound Hsp70 rendered tumor cells more sensitive to the immunological attack mediated by granzyme B and natural killer cells. Our data provide a biological rational for combining anti-inflammatory drugs with immunotherapy in cancer therapy.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NATURAL-KILLER-CELLS; HEAT-SHOCK PROTEINS; MOLECULAR CHAPERONES; GROWTH-INHIBITION; GLYCEMIC CONTROL; CARCINOMA-CELLS; APOPTOSIS; HSP70; ASPIRIN; PIOGLITAZONE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Jul 2021 06:36 |
| Last Modified: | 20 Jul 2021 06:36 |
| URI: | https://pred.uni-regensburg.de/id/eprint/37639 |
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