Transcription factor Fli-1 as a new target for antitumor drug development

Li, Lanlan; Yu, Jia; Cheng, Sha; Peng, Zhi-Lin; Ben‐David, Yaacov; Luo, Heng

doi:10.1016/j.ijbiomac.2022.04.076

Cited by 12 publications

(16 citation statements)

References 123 publications

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“…P-SRC phosphorylates myosin light chain or disrupts the junctions of VE-cadherin and associated proteins such as p120-catenin and β-catenin 19 . In this experiments, SRC was positively correlated with vascular endothelial permeability from 0 to 72 h. Fli-1 is a member of the ETS transcription factor family, which mainly exists in vascular endothelial cells, macrophages, immune cells, hematopoietic system and fibroblasts 20 . It participates in the regulation of inflammatory reaction, embryo development, cell proliferation, differentiation and migration 21 .…”

Section: Discussionmentioning

confidence: 61%

Effect and mechanism of apelin on lipopolysaccharide induced acute pulmonary vascular endothelial barrier dysfunction

Huang

Chen

et al. 2023

Sci Rep

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Vascular endothelial barrier dysfunction is the most prominent manifestation and important cause of mortality in infectious acute lung injury (ALI). Exogenous apelin is effective in ameliorating lipopolysaccharide (LPS)-induced inflammatory response in ALI lungs, reducing exudation of lung tissue and decreasing mortality. This study set out to investigate the association between apelin and Friend leukemia integration-1 (Fli-1) in the prevention and treatment of ALI, and to elucidate the molecular mechanism by which apelin protects the permeability of the vascular endothelial barrier. At the vivo functional level, lung wet/dry weight ratio was used to detect whole lung permeability, evans blue assay and dual fluorescent protein tracking assay were used to detect lung vascular endothelial permeability, HE staining to observe the inflammatory status of lung tissue, and immunofluorescence staining for VE-cadherin expression levels in blood vessels. The changes in inflammatory factors in bronchoalveolar lavage fluid (BALF) were detected by ELASA. Western blot was used to detect the expression level of proteins. qRT-PCR was performed to detect changes in mRNA expression of Fli-1 and adherent junction-related proteins. The correlation analysis of Fli-1 with vascular endothelial permeability and SRC showed that Fli-1 participated in the process of ALI. After preventive and therapeutic treatment of ALI mice with exogenous apelin, Fli-1, APJ, VE-cadherin, phosphorylated-VE-cadherin (p-VE-cadherin) and β-catenin were up-regulated, while SRC, phosphorylated-SRC (p-SRC), VEGF and VEGF-R were down-regulated, which indicated that the stability of vascular endothelial barrier was enhanced. With the use of Fli-1 inhibitor irinotecan, the protective effect of apelin was weakened in various functional indexes, genes and proteins. The lung was maintained at the level of the injury. Our research shows that Fli-1 is involved in the LPS-induced ALI process. The molecular mechanism for apelin in preventing endothelial barrier dysfunction in ALI is through up-regulating Fli-1, thus regulating adherens junction-related proteins, and finally recovering the endothelial barrier function.

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Section: Discussionmentioning

confidence: 61%

Effect and mechanism of apelin on lipopolysaccharide induced acute pulmonary vascular endothelial barrier dysfunction

Huang

Chen

et al. 2023

Sci Rep

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“…The friend leukemia integration 1 protein, an ETS transcription factor, is closely related to cell growth, differentiation, and apoptosis . This protein has already been reported to be activated in various human malignancies. − Therefore, Fli-1 is a potential target for anticancer drug development.…”

Section: Resultsmentioning

confidence: 99%

“…5 It is found to be overexpressed in human leukemia cells, and it is closely related to the occurrence and development of leukemia. 5,6 Up until now, several Fli-1 inhibitors have been identified and are under further investigation in leukemia. 5 Therefore, it is important to discover effective antileukemic drugs by inhibiting Fli-1.…”

mentioning

confidence: 99%

“…Friend leukemia virus-induced erythroleukemia-1 (Fli-1), a proto-oncogene, was first discovered by Prof. BenDavid to be an ETS transcription factor in red leukemia cells . It is found to be overexpressed in human leukemia cells, and it is closely related to the occurrence and development of leukemia. , Up until now, several Fli-1 inhibitors have been identified and are under further investigation in leukemia . Therefore, it is important to discover effective antileukemic drugs by inhibiting Fli-1.…”

mentioning

confidence: 99%

“…5,6 Up until now, several Fli-1 inhibitors have been identified and are under further investigation in leukemia. 5 Therefore, it is important to discover effective antileukemic drugs by inhibiting Fli-1.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Design and Synthesis of Cytotoxic Water-Soluble Rocaglaol Derivatives against HEL Cells by Inhibiting Fli-1

Ge,

Ming,

et al. 2024

J. Nat. Prod.

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Rocaglaol, embedding a cyclopenta[b]benzofuran scaffold, was isolated mainly from the plants of Aglaia and exhibited nanomolar level antitumor activity. However, the drug-like properties of these compounds are poor. To improve the physicochemical properties of rocaglaol, 36 nitrogen-containing phenyl-substituted rocaglaol derivatives were designed and synthesized. These derivatives were tested for the inhibitory effects on three tumor cell lines, HEL, MDA-231, and SW480, using the MTT assay. Among them, 22 derivatives exhibited good cytotoxic activities with IC 50 values between 0.11 ± 0.07 and 0.88 ± 0.02 μM. Fourteen derivatives exhibited stronger cytotoxicity than the positive control, adriamycin. In particular, a water-soluble derivative revealed selective cytotoxic effects on HEL cells (IC 50 = 0.19 ± 0.01 μM). This compound could induce G1 cell cycle arrest and apoptosis in HEL cells. Western blot assays suggested that the water-soluble derivative could downregulate the expression of the marker proteins of apoptosis, PARP, caspase-3, and caspase-9, thus inducing apoptosis. Further CETSA and Western blot studies implied that this water-soluble derivative might be an inhibitor of friend leukemia integration 1 (Fli-1). This water-soluble derivative may serve as a potential antileukemia agent by suppressing the expression of Fli-1.L eukemia, a malignant blood system disorder, is one of the main reasons for deaths worldwide, and its incidence is growing annually. 1 In American, it is reported that the number of leukemia cases could rise to 59 610, and approximately 23 710 people will die from leukemia in 2023. 1 Chemotherapy is a vital method for curing this disease. A variety of drugs, including arabinoside, hydroxyurea, cyclophosphamide, and vincristine,

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FLI-1 is expressed in a wide variety of hematolymphoid neoplasms: a special concern in the differential diagnosis

Cho,

Cha,

Kim

et al. 2024

Clin Exp Med

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Friend Leukemia Virus Integration 1 (FLI-1) is a member of E26 transformation-specific family of transcription factors that participates in hematopoietic and vascular endothelial cell development. Immunohistochemical detection of FLI-1 has been widely used to diagnose vascular tumors or, more evidently, Ewing’s sarcoma. However, the expression pattern of FLI-1 in hematolymphoid neoplasms remains unclear. Therefore, in this study, we aimed to investigate the expression of FLI-1 in these tumors, focusing on high-grade lesions, which presents a diagnostic challenge by mimicking Ewing’s sarcoma. We evaluated the expression FLI-1 in various types of lymphoid and plasmacytic tumors, including 27 plasmablastic lymphomas, 229 diffuse large B-cell lymphomas, 22 precursor T- or B-lymphoblastic lymphomas, 24 angioimmunoblastic-type nodal T-follicular helper cell lymphomas, 52 peripheral T-cell lymphomas, NOS, 18 Burkitt lymphomas, 18 non-gastric lymphomas of mucosa-associated lymphoid tissue, 38 chronic lymphocytic leukemia/small lymphocytic lymphomas, 15 mantle cell lymphomas, 23 gastric MALT lymphomas, 50 plasma cell myelomas, and 38 follicular lymphomas. We calculated the H-scores of FLI-1 immunostaining, ranging from 0 to 200, and used the scores to analyze the clinicopathological significance of FLI-1 statistically. FLI-1 was expressed to varying degrees in all types of hematological tumors. FLI-1 expression was detected in 84.1% of patients (466/554). FLI-1 was highly expressed in precursor T- or B-lymphoblastic lymphomas. Follicular lymphomas exhibited low FLI-1 expression. In plasmablastic lymphoma, 85.2% of the patients were focally positive for FLI-1. FLI-1 expression did not correlate with clinicopathological variables, such as demographic data or disease stage, in patients with plasmablastic lymphoma and diffuse large B-cell lymphoma. However, FLI-1 overexpression was associated with poorer overall survival in patients with plasmablastic lymphoma. This study demonstrates that FLI-1 is expressed in various hematolymphoid neoplasms. FLI-1 expression can lead to diagnostic confusion, especially in small blue round cell tumors, such as lymphoblastic lymphoma, plasmablastic lymphoma, and plasma cell myeloma, when distinguishing tumors positive for CD99 and CD56 without CD3, CD20, or CD45. Our findings also suggested the possibility of FLI-1 as a potential prognostic biomarker for plasmablastic lymphoma.

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Transcription factor Fli-1 as a new target for antitumor drug development

Cited by 12 publications

References 123 publications

Effect and mechanism of apelin on lipopolysaccharide induced acute pulmonary vascular endothelial barrier dysfunction

Effect and mechanism of apelin on lipopolysaccharide induced acute pulmonary vascular endothelial barrier dysfunction

Design and Synthesis of Cytotoxic Water-Soluble Rocaglaol Derivatives against HEL Cells by Inhibiting Fli-1

FLI-1 is expressed in a wide variety of hematolymphoid neoplasms: a special concern in the differential diagnosis

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