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Recent studies suggest that exosomes confer cancer malignancy. However, the relationship between ceramide metabolism and exosome-mediated cancer malignancy is unclear. In this study, we elucidated the role of ceramide metabolism via the SM cycle in exosomes and drug resistance in human leukemia HL-60 and adriamycin-resistant HL-60\/ADR cells. HL-60\/ADR cells showed significantly increased exosome production and release compared with parental chemosensitive HL-60 cells. In HL-60\/ADR cells, increased SM synthase (SMS) activity reduced ceramide levels, although released exosomes exhibited a high ceramide ratio in both HL-60- and HL-60\/ADR-derived exosomes. Overexpression of SMS2 but not SMS1 suppressed intracellular ceramide levels and accelerated exosome production and release in HL-60 cells. Notably, HL-60\/ADR exosomes conferred cell proliferation and doxorubicin resistance properties to HL-60 cells. Finally, microRNA analysis in HL-60 and HL-60\/ADR cells and exosomes showed that miR-484 elevation in HL-60\/ADR cells and exosomes was associated with exosome-mediated cell proliferation. This suggests that intracellular ceramide metabolism by SMS2 regulates exosome production and release, leading to acquisition of drug resistance and enhanced cell proliferation in leukemia cells.<\/jats:p>","DOI":"10.3390\/ijms231810648","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T21:06:52Z","timestamp":1663103212000},"page":"10648","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Ceramide Metabolism Regulated by Sphingomyelin Synthase 2 Is Associated with Acquisition of Chemoresistance via Exosomes in Human Leukemia Cells"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5920-8285","authenticated-orcid":false,"given":"Makoto","family":"Taniguchi","sequence":"first","affiliation":[{"name":"Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Nagaya","sequence":"additional","affiliation":[{"name":"Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Nonoichi 921-8836, Japan"},{"name":"Material Research Department, Shalom Co., Ltd., Oshino 401-0511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Yuyama","sequence":"additional","affiliation":[{"name":"Lipid Biofunction Section, Frontier Research Center for Advanced Material and Life Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai","family":"Kotani","sequence":"additional","affiliation":[{"name":"Department of Hematological Malignancy, Institute of Medical Sciences, Tokai University, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyuki","family":"Igarashi","sequence":"additional","affiliation":[{"name":"Lipid Biofunction Section, Frontier Research Center for Advanced Material and Life Science, Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiro","family":"Okazaki","sequence":"additional","affiliation":[{"name":"Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Nonoichi 921-8836, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrc.2017.96","article-title":"Sphingolipid metabolism in cancer signalling and therapy","volume":"18","author":"Ogretmen","year":"2018","journal-title":"Nat. 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