Synthetic siRNA targeting the breakpoint of <i>EWS</i>/<i>Fli‐1</i> inhibits growth of Ewing sarcoma xenografts in a mouse model

Takigami, Iori; Ohno, Takatoshi; Kitade, Yukio; Hara, Akira; Nagano, Akihito; Kawai, Gou; Saitou, Mitsuru; Matsuhashi, Aya; Yamada, Kazunari; Shimizu, Katsuji

doi:10.1002/ijc.25564

Cited by 39 publications

(31 citation statements)

References 42 publications

(52 reference statements)

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“…A small molecule, YK-4-279, blocking the interaction of EWS/FLI-1 with RNA helicase A inhibits the growth of Ewing sarcoma cells and orthotopic xenografts (39). Targeting of EWS/FLI-1 by RNA interference results in growth inhibition in Ewing sarcoma cells (40,41). However, the specificity, toxicity, and clinical utility of YK-4-279 and the siRNAs remain to be clarified.…”

Section: Discussionmentioning

confidence: 99%

PRAS40 Is a Functionally Critical Target for EWS Repression in Ewing Sarcoma

Huang

Nakai²,

Kuwahara³

et al. 2012

Cancer Research

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Ewing sarcoma family tumors (ESFT) are highly aggressive and highly metastatic tumors caused by a chromosomal fusion between the Ewing sarcoma protein (EWS) with the transcription factor FLI-1. However, expression of the EWS/FLI-1 chimeric oncogene by itself is insufficient for carcinogenesis, suggesting that additional events are required. Here, we report the identification of the Akt substrate PRAS40 as an EWS target gene. EWS negatively regulates PRAS40 expression by binding the 3 0 untranslated region in PRAS40 mRNA. ESFT cell proliferation was suppressed by treatment with an Akt inhibitor, and ESFT cell proliferation and metastatic growth were suppressed by siRNA-mediated PRAS40 knockdown. Furthermore, PRAS40 knockdown was sufficient to reverse an increased cell proliferation elicited by EWS knockdown. In support of a pathologic role for PRAS40 elevation in EFST, we documented inverse protein levels of EWS and PRAS40 in ESFT cells. Together, our findings suggest that PRAS40 promotes the development of ESFT and might therefore represent a novel therapeutic target in this aggressive disease. Cancer Res; 72(5);

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Section: Discussionmentioning

confidence: 99%

PRAS40 Is a Functionally Critical Target for EWS Repression in Ewing Sarcoma

Huang

Nakai²,

Kuwahara³

et al. 2012

Cancer Research

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“…FLI-1 plays a critical role in normal development, hematopoiesis, and oncogenesis by functioning either as a transcriptional activator or repressor [19–22]. 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].…”

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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“…Its inhibition using RNA interference and antisense DNA has been shown to impact cell proliferation in vitro and tumorigenesis in vivo in mouse models (35)(36)(37). However, like all TFs, it has traditionally been regarded as too difficult to target.…”

Section: Discussionmentioning

confidence: 99%

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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Synthetic siRNA targeting the breakpoint of EWS/Fli‐1 inhibits growth of Ewing sarcoma xenografts in a mouse model

Cited by 39 publications

References 42 publications

PRAS40 Is a Functionally Critical Target for EWS Repression in Ewing Sarcoma

PRAS40 Is a Functionally Critical Target for EWS Repression in Ewing Sarcoma

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

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

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