Mechanisms of glucocorticoid resistance in human leukemic cells: implication of abnormal 90 and 70 kDa heat shock proteins.
The unliganded glucocorticoid receptor is a multi-oligomer complex consisting of a ligand-binding protein with which two 90 kDa heat shock proteins (hsp90s) are associated. Upon binding of glucocorticoid to the receptor, the ligand-binding protein, which dissociated from hsp90s, enters the nucleus, binds to a specific site in DNA, and thus transmits signal(s). The 70 kDa heat shock protein (hsp70) also works as a molecular chaperone when the ligand-binding protein enters the nucleus. Regarding the mechanisms of glucocorticoid resistance, a decreased expression of glucocorticoid receptor and a mutant protein with low ligand binding affinity have been reported. In the present study, to address other mechanisms of glucocorticoid resistance, we examined the expression of hsp90 and hsp70 in addition to the number of glucocorticoid-binding sites and their affinity using glucocorticoid-sensitive and -resistant human leukemic cell lines. We showed that two of nine resistant cell lines with normal glucocorticoid-binding proteins express aberrant hsp90 and extremely low hsp70, while another seven resistant cell lines had decreased binding sites with normal hsps. These results suggest that there are at least two independent mechanisms of glucocorticoid resistance in human leukemic cell lines: the decreased ligand-binding sites and the abnormal hsps expression.
Kojika
S
S
Department of Pediatrics, Yamanashi Medical University, Japan.
Sugita
K
K
Inukai
T
T
Saito
M
M
Iijima
K
K
Tezuka
T
T
Goi
K
K
Shiraishi
K
K
Mori
T
T
Okazaki
T
T
Kagami
K
K
Ohyama
K
K
Nakazawa
S
S
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001665:Binding Sites; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005938:Glucocorticoids / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D018931:Antineoplastic Agents, Hormonal; D005938:Glucocorticoids; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone