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Adult T-cell leukemia (ATL) cells are defective in Cer synthesis. ATL is an aggressive neoplasm that develops following infection with human T-cell lymphotropic virus-1 (HTLV-1) where the viral oncogene Tax contributes to the pathogenesis of the disease. ATL cells, resistant to all-trans-retinoic acid, are sensitive to pharmacologically achievable concentrations of the synthetic retinoid ST1926. We studied the effects of ST1926 on Cer pathways in ATL cells. ST1926 treatment resulted in early Tax oncoprotein degradation in HTLV-1-treated cells. ST1926 induced cell death and a dose- and time-dependent accumulation of Cer in malignant T cells. The kinetics and degree of Cer production showed an early response upon ST1926 treatment. ST1926 enhanced de novo Cer synthesis via activation of ceramide synthase CerS(s) without inhibiting dihydroceramide desaturase, thereby accumulating Cer rather than the less bioactive dihydroceramide. Using labeling experiments with the unnatural 17-carbon sphinganine and measuring the generated Cer species, we showed that ST1926 preferentially induces the activities of a distinct set of CerS(s). We detected a delay in cell death response and interruption of Cer generation in response to ST1926 in Molt-4 cells overexpressing Bcl-2. These results highlight the potential role of ST1926 in inducing Cer levels, thus lowering the threshold for cell death in ATL cells.<\/jats:p>","DOI":"10.1042\/bsr20200050","type":"journal-article","created":{"date-parts":[[2020,10,13]],"date-time":"2020-10-13T19:05:32Z","timestamp":1602615932000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Restoration of ceramide<i>de novo<\/i>synthesis by the synthetic retinoid ST1926 as it induces adult T-cell leukemia cell death"],"prefix":"10.1042","volume":"40","author":[{"given":"Botheina","family":"Ghandour","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, American University of Beirut, Lebanon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Pisano","sequence":"additional","affiliation":[{"name":"Biogem Research Institute, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1862-5426","authenticated-orcid":false,"given":"Nadine","family":"Darwiche","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, American University of Beirut, Lebanon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ghassan","family":"Dbaibo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, American University of Beirut, Lebanon"},{"name":"Department of Pediatrics and Adolescent Medicine, Center for Infectious Diseases Research, American University of Beirut, Lebanon"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2020,10,28]]},"reference":[{"key":"2021111620304561100_B1","doi-asserted-by":"publisher","first-page":"2072","DOI":"10.1182\/blood-2014-03-560060","article-title":"Preclinical efficacy of the synthetic retinoid ST1926 for treating adult T-cell leukemia\/lymphoma","volume":"124","author":"El Hajj","year":"2014","journal-title":"Blood"},{"key":"2021111620304561100_B2","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/35106036","article-title":"The promise of retinoids to fight against cancer","volume":"1","author":"Altucci","year":"2001","journal-title":"Nat. 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