FoxO3a and nilotinib-induced erythroid differentiation of CML-BC cells

Wang, Wei; Li, Nannan; Du, Yan; Lv, Feng; Lin, Guo‐Qiang

doi:10.1016/j.leukres.2013.07.001

Cited by 5 publications

(6 citation statements)

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“…Administration of ATO and nilotinib, alone or in combination, significantly suppressed cell proliferation but promoted erythroid differentiation and granulocyte differentiation. These findings are consistent with our previous study, which showed that nilotinib induced erythroid differentiation [ 18 ]. ATO is an anti-leukemic agent that leads to growth suppression and apoptosis induction CML K562 and human leukemia HL60 cells [ 19 - 21 ].…”

Section: Discussionsupporting

confidence: 94%

“…In this study, increased BGT1 and TAL1 levels were detected in CML-BC cells following 72 h of nilotinib treatment. This discrepancy might be due to the prolonged nilotinib incubation (5 d [ 18 ] vs. 3 d) and/or increased drug dose (50 nM [ 18 ] vs. 5 nM) in our previous study. It is possible that TAL1 expression is upregulated during early erythroid differentiation, but downregulated during late stages of differentiation.…”

Section: Discussionmentioning

confidence: 76%

“…Increased BTG1 expression has been observed in erythroid progenitors during erythroid differentiation [ 27 ]. In our previous study, we showed that FoxO3a activation might promote erythroid differentiation of CML-BC cells via down-regulating TAL1 expression [ 18 ]. In this study, increased BGT1 and TAL1 levels were detected in CML-BC cells following 72 h of nilotinib treatment.…”

Section: Discussionmentioning

confidence: 99%

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The effect of nilotinib plus arsenic trioxide on the proliferation and differentiation of primary leukemic cells from patients with chronic myoloid leukemia in blast crisis

Wang

et al. 2015

Cancer Cell International

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AimTo determine the effects of arsenic trioxide (ATO) and nilotinib (AMN107, Tasigna) alone or in combination on the proliferation and differentiation of primary leukemic cells from patients with chronic myeloid leukemia in the blast crisis phase (CML-BC).MethodsCells were isolated from the bone marrow of CML-BC patients and were treated with 1 μM ATO and 5 nM nilotinib, either alone or in combination. Cell proliferation was evaluated using a MTT assay. Cell morphology and the content of hemoglobin were examined with Wright-Giemsa staining and benzidine staining, respectively. The expression of cell surface markers was determined using flow cytometric analysis. The levels of mRNA and protein were analyzed using RT-PCR and Western blotting, respectively.ResultsATO and nilotinib alone or in combination suppressed cell proliferation in a dose- and time-dependent pattern (P < 0.01 vs. control). Drug treatments promoted erythroid differentiation of CML-BC cells, with a decreased nuclei/cytoplasm ratio but increased hemoglobin content and glycophorin A (GPA) expression (P < 0.01 compared with control). In addition, macrophage and granulocyte lineage differentiation was also induced after drug treatment. The mRNA and protein levels of basic helix-loop-helix (bHLH) transcription factor T-cell acute lymphocytic leukemia protein 1 (TAL1) and B cell translocation gene 1 (BTG1) were both upregulated after 3 days of ATO and Nilotinib treatment.ConclusionsOur findings indicated that ATO and nilotinib treatment alone or in combination greatly suppressed cell proliferation but promoted the differentiation of CML-BC cells towards multiple-lineages. Nilotinib alone preferentially induced erythroid differentiation while combined treatment with ATO preferentially induced macrophage and granulocyte lineage differentiation.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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The effect of nilotinib plus arsenic trioxide on the proliferation and differentiation of primary leukemic cells from patients with chronic myoloid leukemia in blast crisis

Wang

et al. 2015

Cancer Cell International

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“…Among the FoxO family, FoxO3a has been shown to be deregulated in several tumor types, including breast cancer [83][84][85] , prostate cancer [86][87][88] , glioblastoma [89] and leukemia [90,91] . Therefore, FoxO3a has been targeted as a way to treat several types of cancers.…”

Section: Foxo3a In Clinical Applicationmentioning

confidence: 99%

FoxO3a and disease progression

Nho

Hergert

2014

WJBC

140

108

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highlighted as a critical protein that regulates numerous cell functions from proliferation/apoptosis to stressresistance and aging. FoxO3a has been found to be deregulated in several diseases and FoxO3a targeting approaches are currently underway to treat various types of cancers. This review will describe the current concept of FoxO3a's pathological role in various diseases and elucidate the regulatory mechanisms involved. It will also provide the clinical significance and strategies to target FoxO3a to limit the progression of human diseases. INTRODUCTIONForkhead box O (FoxO) transcription factors are the human homologues of the C. elegans transcription factor DAF-16 and share a highly conserved 110-amino acid DNA binding domain, forkhead box or winged-helix domain [1,2] . Forkhead box proteins comprise more than 100 members in humans, classified from FOXA to FOXR [3][4][5] . Members of class O share the characteristic of being regulated by the insulin/PI3K/Akt signaling pathway [4] . Four principal members of the mammalian FoxO subfamily, FoxO1, FoxO3a, FoxO4 and FoxO6 have been previously described [3] . Although they seem to bind a common set of DNA sites, FoxO6 is mainly specific to neurons, while the other 3 FoxO family members are expressed in most tissues. These FoxO members are linked to cell survival, cellular proliferation and DNA damage repair response [5,6] . Among them, FoxO3a has recently been studied extensively as a crucial protein that is involved in the regulation of several essential cellular functions (see page 349). Prior studies have shown that FoxO3a functions as a tumor suppressor by regulating expression of genes in- AbstractThe Forkhead box O (FoxO) family has recently been highlighted as an important transcriptional regulator of crucial proteins associated with the many diverse functions of cells. So far, FoxO1, FoxO3a, FoxO4 and FoxO6 proteins have been identified in humans. Although each FoxO family member has its own role, unlike the other FoxO families, FoxO3a has been extensively studied because of its rather unique and pivotal regulation of cell proliferation, apoptosis, metabolism, stress management and longevity. FoxO3a alteration is closely linked to the progression of several types of cancers, fibrosis and other types of diseases. In this review, we will examine the function of FoxO3a in disease progression and also explore FoxO3a's regulatory mechanisms. We will also discuss FoxO3a as a potential target for the treatment of several types of disease.

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“…Hu and colleagues have shown that FoxO3a is linked to the poor survival of patients with breast tumors (6). In addition to breast cancer (7)(8)(9), FoxO3a has been shown to be involved in several other tumor types, including prostate cancer, glioblastoma and leukemia (10)(11)(12)(13)(14)(15). The role of FoxO3a in cancer progression is primarily attributed to the two most significant cellular processes regulated by FoxO3a: i) FoxO3a activation increases the levels of cell cycle inhibitor proteins p21 and p27, both of which subsequently suppress the G1 to S cell cycle transition (16)(17)(18), and ii) the expression of FoxO3a leads to pro-apoptosis (19,20) through the modulation of the expression of its target genes.…”

Section: Introductionmentioning

confidence: 99%

FoxO3a mediates glioma cell invasion by regulating MMP9 expression

Peng

Zhang

et al. 2016

Oncology Reports

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The role of FoxO3a in glioma progression is poorly defined. Herein, we show that silencing FoxO3a in U251 cells leads to decreased invasive migration and proliferation, while ectopic expression of FoxO3a in U87 cells with weak endogenous FoxO3a protein levels enhances invasion and proliferation. To further investigate the mechanism by which FoxO3a promotes invasion, we detected key members of the matrix metalloproteinases (MMPs) that are associated with invasion. Our findings showed that, among these MMP members, only FoxO3a induced MMP9 expression, and MMP9 overexpression reversed the effect that silencing FoxO3a had on the attenuation of cell invasion. Taken together, these data link FoxO3a to the promotion of metastasis in glioma cells.

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FoxO3a and nilotinib-induced erythroid differentiation of CML-BC cells

Cited by 5 publications

References 29 publications

The effect of nilotinib plus arsenic trioxide on the proliferation and differentiation of primary leukemic cells from patients with chronic myoloid leukemia in blast crisis

The effect of nilotinib plus arsenic trioxide on the proliferation and differentiation of primary leukemic cells from patients with chronic myoloid leukemia in blast crisis

FoxO3a and disease progression

FoxO3a mediates glioma cell invasion by regulating MMP9 expression

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