NFkappaB modulators in a model of glucocorticoid resistant, childhood acute lymphoblastic leukemia.
Glucocorticoids (GCs) are pivotal agents in the treatment of childhood acute lymphoblastic leukaemia (ALL) but the molecular basis of GC-resistance remains unclear. Expression-array studies have shown that commonly upregulated genes associated with GC-sensitivity include GR, glucocorticoid-induced leucine zipper (GILZ) and IkappaBalpha, which all negatively interact with components of the pro-survival NFkappaB pathway and therefore may be critical determinants of GC-sensitivity. We have investigated these regulators and their effect on NFkappaB activity in GC-resistant descendents of the B-lineage ALL cell line, PreB 697. We show that while differential up regulation of the modulators (GILZ, GR and IkappaBalpha) was demonstrated in GC-sensitive compared to GC-resistant sub-lines, this was not coupled with altered nuclear translocation or functionality of the RelA, p50 or c-Rel subunits of NFkappaB. Thus, GC-resistance in the PreB 697 cell line model is not mediated by NFkappaB, however further investigation of the impact of these GC-sensitive associated proteins on other survival pathways, such as the RAS-RAF-MEK-ERK pathway, is warranted.
Nicholson
Lindsay
L
Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, Tyne and Wear NE2 4HH, UK.
Hall
Andrew G
AG
Redfern
Christopher P
CP
Irving
Julie
J
D000293:Adolescent; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D020672:I-kappa B Proteins / Q000502:physiology; D007223:Infant; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011965:Receptors, Glucocorticoid / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology
D005938:Glucocorticoids; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011965:Receptors, Glucocorticoid; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha