Activating Transcription Factor 5 Promotes Neuroblastoma Metastasis by Inducing Anoikis Resistance.

Autor:	Banerjee D; Department of Pediatrics, Columbia University Irving Medical Center, New York, New York., Boboila S; Department of Pediatrics, Columbia University Irving Medical Center, New York, New York.; Department of Radiation Oncology, Columbia University Irving Medical Center, New York, New York., Okochi S; Department of Surgery, Columbia University Irving Medical Center, New York, New York., Angelastro JM; Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, California., Kadenhe-Chiweshe AV; Department of Surgery, Weill Cornell Medicine, New York, New York., Lopez G; Department of Systems Biology, Columbia University Irving Medical Center, New York, New York., Califano A; Department of Systems Biology, Columbia University Irving Medical Center, New York, New York.; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York., Connolly EP; Department of Radiation Oncology, Columbia University Irving Medical Center, New York, New York.; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York., Greene LA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York., Yamashiro DJ; Department of Pediatrics, Columbia University Irving Medical Center, New York, New York.; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2023 Dec 12; Vol. 3 (12), pp. 2518-2530.
DOI:	10.1158/2767-9764.CRC-23-0154
Abstrakt:	MYCN-amplified neuroblastoma often presents as a highly aggressive metastatic disease with a poor prognosis. Activating transcription factor 5 (ATF5) is implicated in neural cell differentiation and cancer cell survival. Here, we show that ATF5 is highly expressed in patients with stage 4 high-risk neuroblastoma, with increased expression correlating with a poorer prognosis. We demonstrated that ATF5 promotes the metastasis of neuroblastoma cell lines in vivo. Functionally, ATF5 depletion significantly reduced xenograft tumor growth and metastasis of neuroblastoma cells to the bone marrow and liver. Mechanistically, ATF5 endows tumor cells with resistance to anoikis, thereby increasing their survival in systemic circulation and facilitating metastasis. We identified the proapoptotic BCL-2 modifying factor (BMF) as a critical player in ATF5-regulated neuroblastoma anoikis. ATF5 suppresses BMF under suspension conditions at the transcriptional level, promoting anoikis resistance, whereas BMF knockdown significantly prevents ATF5 depletion-induced anoikis. Therapeutically, we showed that a cell-penetrating dominant-negative ATF5 peptide, CP-d/n-ATF5, inhibits neuroblastoma metastasis to the bone marrow and liver by inducing anoikis sensitivity in circulating tumor cells. Our study identified ATF5 as a metastasis promoter and CP-d/n-ATF5 as a potential antimetastatic therapeutic agent for neuroblastoma. Significance: This study shows that resistance to anoikis in neuroblastoma is mediated by ATF5 and offers a rationale for targeting ATF5 to treat metastatic neuroblastoma. (© 2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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