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15417786mcr150127-sup-146691_1_supp_3100443_nszvbt.pptx (58.01 kB)

Supplementary Figure S4 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. Lam

The resistant REH cells were treated with LY294002 (30μM), PI-103 (30μM) or Rapamycin (30μM) in the absence or presence of dexamethasone (1μM). Cell viability analysis was performed after 48 h using MTT assay. (t-test 2-tailed: treated verses untreated cells) *significant p<0.05, ** very significant p<0.01 and ns: 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.