Drug-mediated inhibition of Fli-1 for the treatment of leukemia

Yj, Li; Zhao, Xiaojun; Lm, Vecchiarelli-Federico; Y, Li; Datti, Alessandro; Cheng, Yong; Ben‐David, Yaacov

doi:10.1038/bcj.2011.52

Cited by 38 publications

(80 citation statements)

References 26 publications

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“…This activity profile was suggestive of changes in Ca 2ϩ homeostasis and/or signaling (23)(24)(25)(26). Interestingly, previous high throughput screens aimed at identifying inhibitors of Fli-1 in leukemia led to the identification of calcium ionophores including calcimycin and thapsigargin as hits (27). Calcimycin and thapsigargin were also found to moderately inhibit EWS-FLI1 induced luciferase reporter activity in our screen suggesting that EA may also exert its effects through modulation of intracellular calcium levels.…”

Section: Waf1/cif1supporting

confidence: 56%

Englerin A Inhibits EWS-FLI1 DNA Binding in Ewing Sarcoma Cells

Caropreso

Darvishi

Turbyville

et al. 2016

Journal of Biological Chemistry

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High-throughput screening of extracts from plants, marine, and micro-organisms led to the identification of the extract from the plant Phyllanthus engleri as the most potent inhibitor of EWS-FLI1 induced luciferase reporter expression. Testing of compounds isolated from this extract in turn led to the identification of Englerin A (EA) as the active constituent of the extract. EA induced both necrosis and apoptosis in Ewing cells subsequent to a G2M accumulation of cells in the cell cycle. It also impacted clonogenic survival and anchorage-independent proliferation while also decreasing the proportion of chemotherapy-resistant cells identified by high ALDH activity. EA also caused a sustained increase in cytosolic calcium levels. EA appears to exert its effect on Ewing cells through a decrease in phosphorylation of EWS-FLI1 and its ability to bind DNA. This effect is mediated, at least in part, through a decrease in the levels of the calcium-dependent protein kinase PKC-␤I after a transient up-regulation.The hallmark that defines the Ewing sarcoma family of tumors is the presence of non-random chromosomal rearrangements between the Ewing sarcoma breakpoint region 1 gene (EWS) 2 located on chromosome 22q12 and genes of the E26 transformation-specific sequence (ETS) family of transcription factors. Reciprocal chromosomal translocations, t(11; 22) (q24;q12), that result in the fusion of the transactivational domain of EWS and the DNA binding domain of FLI1, an ETS transcription factor, generating the chimeric EWS-FLI1 fusion transcript underlie an overwhelming majority of cases of Ewing sarcoma (1). The disease arises in less than 3 per million people under the age of 20, with 90% of all cases being found in patients between 5 and 25 years of age (2). Prior to the advent of chemotherapy, up to 90% of patients succumbed to the disease when only surgery and/or radiation were used. Current standard treatment constitutes combination chemotherapy along with surgery and/or radiation. This approach has had a positive impact on event-free survival and overall survival. However, in 27% of patients diagnosed with localized disease, this treatment modality still fails to improve overall survival (3). Furthermore, 15-25% of patients present with metastases upon diagnosis and the cure rate among this group is below 20% (4). Overall the long-term cure rate in children and adolescents with Ewing sarcoma still remains under 60% (5). Various reports show the aberrant transcription factor EWS-FLI1 is a key contributor in the tumorigenesis and progression of Ewing sarcoma (6, 7). The discovery of molecules that modulate its activity are expected to not only provide a better understanding of the biology behind the disease but are also expected to lead to the development of chemotherapeutic agents targeting the disease. Herein we describe results from a mode-of-action study undertaken using a compound identified as an inhibitor from a plant extract in a primary high-throughput screen (HTS). Experimental ProceduresReagents-Synthetic EWS-...

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Section: Waf1/cif1supporting

confidence: 56%

Englerin A Inhibits EWS-FLI1 DNA Binding in Ewing Sarcoma Cells

Caropreso

Darvishi

Turbyville

et al. 2016

Journal of Biological Chemistry

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“…Knocking down FLI-1 expression in cancer cells leads to growth inhibition and cell death, demonstrating a possible therapeutic approach to induce tumor suppression [23, 24]. Anti- FLI-1 compounds have demonstrated strong anti-leukemic activity in a mouse model that over-expresses FLI-1 , making it possible to target FLI-1 as an anti-tumor treatment [25]. However the role of the miR-145/ FLI-1 pathway has not been elucidated in osteosarcoma.…”

Section: Introductionmentioning

confidence: 99%

miR-145 promotes osteosarcoma growth by reducing expression of the transcription factor friend leukemia virus integration 1

Liang

et al. 2016

Oncotarget

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Osteosarcoma (OS) is the most common malignant bone tumor in children and young adults. miR-145 is a microRNA highly expressed in vascularized tissues and has been widely studied in cancers. In this study, we explored the expression and function of miR-145 in OS. We found that miR-145 was consistently under-expressed in OS tissues and cell lines as compared to normal bone tissues and osteoblast cells. Ectopic expression of miR-145 in OS cells inhibited their proliferation and migration and induced apoptosis. miR-145 targets a putative microRNA regulatory element (MRE) in the 3′-UTR of friend leukemia virus integration 1 gene (FLI-1), and its abundance was inversely related to FLI-1 expression in OS tissues and cell lines. miR-145 decreased expression FLI-1 protein and mRNA, but mutation of the miR-145 MRE sequence in the FLI-1 3′-UTR abolished the activity of miR-145 in a reporter assay. Restored expression of FLI-1 diminished miR-145-mediated suppression of tumor progression. These results suggest that miR-145 acts as a tumor suppressor by directly reducing expression of FLI-1, and that the miR-145/FLI-1 pathway is important for tumor progression in OS.

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“…Anti-Fli-1 compounds had been discovered and demonstrated strong anti-leukemic activity in a mouse erythroleukemia model that overexpresses Fli-1, making it possible for targeting Fli-1 as a potent treatment strategy [23]. …”

Section: Introductionmentioning

confidence: 99%

Oncogenic Fli-1 is a potential prognostic marker for the progression of epithelial ovarian cancer

Song

et al. 2014

BMC Cancer

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BackgroundOvarian cancer is the most lethal gynecologic malignancy, but its etiology remains poorly understood. This study investigated the role of Fli-1 in ovarian carcinogenesis and disease survival.MethodsFli-1 protein expression was evaluated by immunohistochemistry in 104 primary epithelial ovarian cancer (EOC) patients with known follow-up data and 20 controls. Correlation between Fli-1 expression and clinical characteristics was evaluated with the logistic regression. Kaplan Meier analysis was used to assess the impact of Fli-1 expression on overall survival (OS) and disease-free survival (DFS). Cell proliferation and migration assay were used to explore the function of Fli-1 in ovarian cancer cells.ResultsFli-1 was expressed in 74% cases and up-regulated in EOC tissues compared with normal control tissues (p< 0.05). The high expression of Fli-1 was significantly associated with advanced tumor stage, positive lymph nodal involvement, and poor OS and DFS (p< 0.05). Further analysis showed Fli-1 is an independent prognostic factor for OS and DFS. Down-regulation of Fli-1 inhibited cell proliferation but did not affect cell migration in SKOV3 cells.ConclusionsThis study revealed that Fli-1 played an essential role in the development and progression of ovarian cancers. Its overexpression is intimately related to malignant phenotypes and poor clinical outcome, suggesting that Fli-1 is a potential prognostic marker and therapeutic molecular target in ovarian cancer.

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Drug-mediated inhibition of Fli-1 for the treatment of leukemia

Cited by 38 publications

References 26 publications

Englerin A Inhibits EWS-FLI1 DNA Binding in Ewing Sarcoma Cells

Englerin A Inhibits EWS-FLI1 DNA Binding in Ewing Sarcoma Cells

miR-145 promotes osteosarcoma growth by reducing expression of the transcription factor friend leukemia virus integration 1

Oncogenic Fli-1 is a potential prognostic marker for the progression of epithelial ovarian cancer

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