Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1
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 t...
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| Format: | Article |
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MDPI AG
2020-04-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/4/886 |
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| author | Ling-Wei Hii Felicia Fei-Lei Chung Chun Wai Mai Zong Yang Yee Hong Hao Chan Vijay Joseph Raja Noah Elias Dephoure Nigel J. Pyne Susan Pyne Chee-Onn Leong |
| author_facet | Ling-Wei Hii Felicia Fei-Lei Chung Chun Wai Mai Zong Yang Yee Hong Hao Chan Vijay Joseph Raja Noah Elias Dephoure Nigel J. Pyne Susan Pyne Chee-Onn Leong |
| author_sort | Ling-Wei Hii |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T20:40:16Z |
| format | Article |
| id | doaj.art-9ced413142d1486c84837cbe544b8c98 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T20:40:16Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-9ced413142d1486c84837cbe544b8c982023-11-19T20:43:00ZengMDPI AGCells2073-44092020-04-019488610.3390/cells9040886Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1Ling-Wei Hii0Felicia Fei-Lei Chung1Chun Wai Mai2Zong Yang Yee3Hong Hao Chan4Vijay Joseph Raja5Noah Elias Dephoure6Nigel J. Pyne7Susan Pyne8Chee-Onn Leong9Centre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, MalaysiaMechanisms of Carcinogenesis Section (MCA), Epigenetics Group (EGE) International Agency for Research on Cancer, World Health Organization, 69372 Lyon, FranceCentre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, MalaysiaCentre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, MalaysiaCentre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, MalaysiaDepartment of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USADepartment of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USAStrathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, Scotland, UKStrathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, Scotland, UKCentre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, MalaysiaCancer 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.https://www.mdpi.com/2073-4409/9/4/886cancer stem cellssphingosine kinaseSTAT1mammospheresdrug synergismsphingolipids |
| spellingShingle | Ling-Wei Hii Felicia Fei-Lei Chung Chun Wai Mai Zong Yang Yee Hong Hao Chan Vijay Joseph Raja Noah Elias Dephoure Nigel J. Pyne Susan Pyne Chee-Onn Leong Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1 Cells cancer stem cells sphingosine kinase STAT1 mammospheres drug synergism sphingolipids |
| title | Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1 |
| title_full | Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1 |
| title_fullStr | Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1 |
| title_full_unstemmed | Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1 |
| title_short | Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1 |
| title_sort | sphingosine kinase 1 regulates the survival of breast cancer stem cells and non stem breast cancer cells by suppression of stat1 |
| topic | cancer stem cells sphingosine kinase STAT1 mammospheres drug synergism sphingolipids |
| url | https://www.mdpi.com/2073-4409/9/4/886 |
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