Dexamethasone-induced inositol 1,4,5-trisphosphate receptor elevation in murine lymphoma cells is not required for dexamethasone-mediated calcium elevation and apoptosis.
Glucocorticosteroid hormones, including dexamethasone, have diverse effects on immature lymphocyte function that ultimately lead to cell death. Previous studies established that glucocorticoid-induced alterations in intracellular calcium homeostasis promote apoptosis, but the mechanism by which glucocorticoids disrupt calcium homeostasis is unknown. Through gene expression array analysis, we found that dexamethasone induces a striking elevation of inositol 1,4,5-trisphosphate receptor (IP(3)R) levels in two murine lymphoma cell lines, WEHI7.2 and S49.A2. IP(3)R elevation was confirmed at both mRNA and protein levels. However, there was not a strong correlation between IP(3)R elevation and altered calcium homeostasis in terms of either kinetics or dose response. Moreover, IP(3)R knockdown, by either antisense or small interfering RNA, did not prevent either calcium disruption or apoptosis. Finally, DT40 lymphoma cells lacking all three IP(3)R isoforms were just as sensitive to dexamethasone-induced apoptosis as wild-type DT40 cells expressing all three IP(3)R isoforms. Thus, although alterations in intracellular calcium homeostasis contribute to glucocorticoid-induced apoptosis, these calcium alterations are not directly attributable to IP(3)R elevation.
Davis
Michael C
MC
Division of Hematology/Oncology, Departments of Medicine and Pharmacology, Comprehensive Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
McColl
Karen S
KS
Zhong
Fei
F
Wang
Zhengqi
Z
Malone
Michael H
MH
Distelhorst
Clark W
CW
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000096:biosynthesis*; D008223:Lymphoma / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D020033:Protein Isoforms; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation
D018931:Antineoplastic Agents, Hormonal; D053496:Inositol 1,4,5-Trisphosphate Receptors; D020033:Protein Isoforms; D012333:RNA, Messenger; D003907:Dexamethasone; D002118:Calcium