{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:29:23Z","timestamp":1791199763240,"version":"4.2.0"},"reference-count":91,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,4]],"date-time":"2020-04-04T00:00:00Z","timestamp":1585958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003093","name":"Ministry of Higher Education, Malaysia","doi-asserted-by":"publisher","award":["FRGS\/1\/2016\/SKK08\/IMU\/01\/1"],"award-info":[{"award-number":["FRGS\/1\/2016\/SKK08\/IMU\/01\/1"]}],"id":[{"id":"10.13039\/501100003093","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003093","name":"Ministry of Higher Education, Malaysia","doi-asserted-by":"publisher","award":["ERGS\/1\/2013\/SKK01\/IMU\/02\/1"],"award-info":[{"award-number":["ERGS\/1\/2013\/SKK01\/IMU\/02\/1"]}],"id":[{"id":"10.13039\/501100003093","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cancer stem cells (CSCs) represent rare tumor cell populations capable of self-renewal, differentiation, and tumor initiation and are highly resistant to chemotherapy and radiotherapy. Thus, therapeutic approaches that can effectively target CSCs and tumor cells could be the key to efficient tumor treatment. In this study, we explored the function of SPHK1 in breast CSCs and non-CSCs. We showed that RNAi-mediated knockdown of SPHK1 inhibited cell proliferation and induced apoptosis in both breast CSCs and non-CSCs, while ectopic expression of SPHK1 enhanced breast CSC survival and mammosphere forming efficiency. We identified STAT1 and IFN signaling as key regulatory targets of SPHK1 and demonstrated that an important mechanism by which SPHK1 promotes cancer cell survival is through the suppression of STAT1. We further demonstrated that SPHK1 inhibitors, FTY720 and PF543, synergized with doxorubicin in targeting both breast CSCs and non-CSCs. In conclusion, we provide important evidence that SPHK1 is a key regulator of cell survival and proliferation in breast CSCs and non-CSCs and is an attractive target for the design of future therapies.<\/jats:p>","DOI":"10.3390\/cells9040886","type":"journal-article","created":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T03:58:39Z","timestamp":1586231919000},"page":"886","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0537-3693","authenticated-orcid":false,"given":"Ling-Wei","family":"Hii","sequence":"first","affiliation":[{"name":"Centre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia"},{"name":"School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia"},{"name":"School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1043-4948","authenticated-orcid":false,"given":"Felicia Fei-Lei","family":"Chung","sequence":"additional","affiliation":[{"name":"Mechanisms of Carcinogenesis Section (MCA), Epigenetics Group (EGE) International Agency for Research on Cancer, World Health Organization, 69372 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6532-184X","authenticated-orcid":false,"given":"Chun Wai","family":"Mai","sequence":"additional","affiliation":[{"name":"Centre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia"},{"name":"School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zong Yang","family":"Yee","sequence":"additional","affiliation":[{"name":"Centre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia"},{"name":"School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong Hao","family":"Chan","sequence":"additional","affiliation":[{"name":"Centre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia"},{"name":"School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay Joseph","family":"Raja","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah Elias","family":"Dephoure","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel J.","family":"Pyne","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, Scotland, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Pyne","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, Scotland, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6353-9703","authenticated-orcid":false,"given":"Chee-Onn","family":"Leong","sequence":"additional","affiliation":[{"name":"Centre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia"},{"name":"School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1038\/nm.4409","article-title":"Cancer stem cells revisited","volume":"23","author":"Batlle","year":"2017","journal-title":"Nat. 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