15417786mcr150127-sup-146691_1_supp_3100442_nszvbt.pptx (235.04 kB)
Supplementary Figure S3 from FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL
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posted on 2023-04-03, 16:29 authored by Francesca Consolaro, Sadaf Ghaem-Maghami, Roberta Bortolozzi, Stefania Zona, Mattaka Khongkow, Giuseppe Basso, Giampietro Viola, Eric W.-F. LamSirtinol but not EX527 or PDF-170 significantly enhances ithe cytotoxic and cytostatic function of dexamethasone in B-ALL cell lines REH and RS4;11 cells were treated with the a range of concentrations of SIRT inhibitors (0-100μM) and/or dexamethasone. Cell viability analysis was performed after 24, 48 and 72 h using MTT assay. A) Sintinol (SIRT1/2/6 inhibitor); B) EX527 (SIRT1 inhibitor); C) PDF-170 (SIRT2 inhibitor). (t-test: Sirtinol with 1μM dexamethasone verses dexamethasone at 1μM) *significant p<0.05, ** very significant p<0.01 and no marker: not significant.
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ARTICLE ABSTRACT
Glucocorticoids are widely used to treat B acute lymphoblastic leukemia (B-ALL); however, the molecular mechanism underlying glucocorticoid response and resistance is unclear. In this study, the role and regulation of FOXO3a in mediating the dexamethasone response in B-ALL were investigated. The results show that FOXO3a mediates the cytotoxic function of dexamethasone. In response to dexamethasone, it was found that FOXO3a translocates into the nucleus, where it induces the expression of downstream targets, including p27Kip1 and Bim, important for proliferative arrest and cell death in the sensitive RS4;11 and SUP-B15 B-ALL cells. FOXO3a activation by dexamethasone is mediated partially through the suppression of the PI3K/Akt signaling cascade. Furthermore, two posttranslational modifications were uncovered, phosphorylation on Ser-7 and acetylation on Lys-242/5, that associated with FOXO3a activation by dexamethasone. Immunoblot analysis showed that the phosphorylation on Ser-7 of FOXO3a is associated with p38/JNK activation, whereas the acetylation on Lys-242/5 is correlated with the downregulation of SIRT1/2/6 and the induction of the acetyltransferase CBP/p300. Collectively, these results indicate that FOXO3a is essential for dexamethasone response in B-ALL cells, and its nuclear translocation and activation is associated with its phosphorylation on Ser-7 and acetylation on Lys-242/245. These posttranslational events can be exploited as biomarkers for B-ALL diagnosis and as drug targets for B-ALL treatment, particularly for overcoming the glucocorticoid resistance.Implications: FOXO3a and its posttranslational regulation are essential for dexamethasone response, and targeting FOXO3a and sirtuins may enhance the dexamethasone-induced cytotoxicity in B-ALL cells. Mol Cancer Res; 13(12); 1578–90. ©2015 AACR.Usage metrics
Keywords
Cell CycleSignal transduction pathwaysCell Death And SenescenceReceptor-coupled signaling to apoptosisSurvival factorsCell SignalingDrug MechanismsCell cycle mechanisms of anticancer drug actionCellular responses to anticancer drugsDrug ResistanceNovel mechanismsRegulation of gene expression in drug resistanceReversal of drug resistanceHematological CancersLeukemias
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