Active FKHRL1 overcomes imatinib resistance in chronic myelogenous leukemia‐derived cell lines via the production of tumor necrosis factor‐related apoptosis‐inducing ligand

Abstract

FKHRL1 (also calledFOXO3a

BCR–ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients

“…It is known that TRAIL frequently induces apoptosis in BCR-ABL-positive leukemia cells (Uno et al, 2003) and it was suggested that TRAIL production can overcome Imatinib mesylate resistance in CML cell lines (Kikuchi et al, 2007). This information is in agreement with our data showing that K562 cells with an artificial reduction in PRAME or EZH2 expression are more sensitive to Imatinib treatment owing to increased TRAIL expression.…”

Loss of memory B cells during chronic HIV infection is driven by Foxo3a- and TRAIL-mediated apoptosis

“…The manipulation or induction of Foxo3a activity by anticancer drugs such as imatinib or the use of recombinant TRAIL has proven efficient in treating resistant cancers and autoimmune diseases (59)(60)(61). Conversely, interfering with Foxo3a and TRAIL signaling, alone or in combination with HAART, could rescue both T and B cell functions and could also restore global Ab responses including those elicited against HIV, thus improving the success of therapeutic vaccines against this and other infections.…”

OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins

“…FoxO3a activation in a colon carcinoma cell line also prevents cellular proliferation through Myc target genes that involve the Mad/Mxd family of transcriptional repressors [50]. In addition, treatment of chronic myelogenous leukemia cell lines with the Bcr-Abl tyrosine kinase inhibitor imatinib requires FoxO3a activation to antagonize cell proliferation and promote apoptotic cell death through increased TRAIL production [51]. By contrast, loss of FoxO3a activity in association with cMyc, p27 and nuclear factor-κB (NF-κB) can result in cell cycle induction and malignant transformation of mouse cells in the presence of oncogene activation [52].…”

“…FoxO3a activation can inhibit cell cycle progression and proliferation of tumor growth in colon carcinoma cell lines [50]. Several studies also suggest that the loss of FoxO3a activity in primary leukemic cells might participate in oncogenic transformation in B-chronic lymphocytic leukemia [75], in the progression of chronic myelogenous leukemia cell lines [51] and in the transformation of cells into Kaposi's sarcoma [76]. Interestingly, loss of functional FoxO3a in human ovarian cancer cell lines can limit the sensitivity of ovarian cancer cells to chemotherapy such as cisplatin [77], which suggests that FoxO proteins might be responsible for altered treatment outcomes in the presence of combined therapeutic approaches.…”

“…These interconnected pathways involve IκB kinase (IKK), IκB, protein 14-3-3, growth-arrest and DNA-damage-response protein 45 (Gadd45), Fas ligand (Fas L), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), the BH3-only proteins Noxa and Bim, p53, c-myc, p27, mitochondrial membrane potential (Mito), cytochrome c (Cyto-c) and caspases. Foxo3a depletion leads to oocyte death and infertility [13] Overexpression of Foxo3a leads to oocyte growth retardation, follicular failure and anovulation [14] Mutations in FOXO1a and FOXO3a lead to clinical premature ovarian failure [83] Inflammatory and immune disease Absence of Foxo3a leads to lymphoproliferation, organ inflammation, enhanced helper Tcell activity [15] Increased FOXO3a levels lead to changes in T cell response and activity [88] Foxo3a is necessary for neutrophil activation [16] Rheumatoid arthritis leads to increased post-translational phosphorylation of FOXO1, FOXO3a and FOXO4 in synovial tissue biopsy [84] Progenitor cells in the hematopoietic and nervous systems Erythropoietin leads to the inhibition of Foxo3a activity [19,20,44] Erythropoietin-Foxo3a association promotes erythropoiesis [ Loss of FoxO1 and FoxO3a promotes breast and prostate cancer growth whereas activity of FoxO1 and FoxO3a blocks tumor progression [69][70][71][72] FoxO3a activation leads to inhibition of cell cycle progression and prevents proliferation of human colon cancer cells [50] Loss of FoxO3a activity leads to oncogenic transformation in hematopoietic derived cancers and Kaposi's sarcoma [51,75,76] Changes in FoxO3a activity can alter the sensitivity of tumor cells to chemotherapeutic agents [77] Nomenclature: 'FoxO' pertains to cell culture, tissue or animal studies; 'FOXO' pertains to human studies.…”