title: Involvement of the glucocorticoid receptor in stress-induced apoptosis of leukemic cells.
abstract: Glucocorticoid (GC) hormones induce apoptosis in lymphoid and leukemic cells by binding and activating cytosolic GC receptors. Because physiological stress often causes hormone-free GC receptor activation, we have investigated if stress-induced apoptosis of lymphoid cells is also mediated by the activation of the GC receptor pathway. In S49 T lymphoma cells, heat shock and deprivation of growth factors or nutrients caused nuclear translocation and loss of agonist binding capacity of GC receptors, similar to that in cells incubated with the glucocorticoid dexamethasone (DEX). In variant S49 H.2 cells, cross-resistance to DEX, temperature shocks and growth factor deprivation were associated with a higher threshold for hormone-dependent and -independent receptor activation in situ and with impaired in vitro activation of cytosolic receptors. Cross-resistance to DEX, low serum and heat shock was abrogated, however, by pharmacological sensitization of GC receptor activation with the drug meta-iodobenzylguanidine (MIBG). Sensitive S49 cells and resistant variants did not differ in the expression levels of the apoptosis-regulating genes bax, bad, bcl-X and bcl-2, the status of the p53 gene nor in a different requirement for the growth factors II-2, IL-4 or IL-9. The results suggest that ligand-independent activation of the GC receptor is a central signalling and controlling event in some forms of stress-induced apoptosis, assigning a novel function to the GC receptor in the regulation of lymphoid and leukemic cell numbers.
authors.affiliation: Department of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam.
authors.forename: L A
authors.initials: LA
authors.lastname: Smets
authors.forename: G
authors.initials: G
authors.lastname: Salomons
authors.forename: H
authors.initials: H
authors.lastname: Van Rooij
authors.forename: J
authors.initials: J
authors.lastname: van den Berg
mesh_terms: D019797:3-Iodobenzylguanidine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000096:biosynthesis; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005434:Flow Cytometry; D006358:Hot Temperature; D007700:Kinetics; D016399:Lymphoma, T-Cell / Q000473:pathology*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology*; D013312:Stress, Physiological; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
chemical_list: C494820:Bad protein, mouse; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011965:Receptors, Glucocorticoid; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D019797:3-Iodobenzylguanidine; D003907:Dexamethasone