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 tumour cell populations capable of self-renewal, differentiation and tumour initiation, and are highly resistant to chemotherapy and radiotherapy. Thus, therapeutic approaches which can effectively target CSCs and tumour cells could be the key towards efficient tumour treatment. In this study, we explored the function of SPHK1 in breast CSCs and non-CSCs. We showed that RNAi-mediated knockdown of SPHK1 inhibits cell proliferation and induces apoptosis in both breast CSCs and non-CSCs, while ectopic expression of SPHK1 enhances breast CSC survival and mammosphere forming efficiency. We identified STAT1 and IFN signalling 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 demonstrate 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