Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1.

Ling-Wei Hii,Zong Yang Yee,Chun Wai Mai,Chun Wai Mai,Chee-Onn Leong,Vijay Joseph Raja,Nigel J Pyne,Susan Pyne,Hong Hao Chan,Felicia Fei-Lei Chung,Noah Elias Dephoure

doi:10.3390/cells9040886

Abstract

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.

Highlights

Breast cancer stem cells (CSCs) represent a subset of cancer cells with the capabilities of self-renewal and differentiation [1,2]
To investigate whether the Sphingosine kinase (SPHK)-sphingosine 1-phosphate (S1P) axis is altered in breast Cancer stem cells (CSCs), we evaluated the basal expression levels of SPHK1, phosphorylated SPHK1, and SPHK2 in a panel of breast CSCs derived from MCF-7, SKBR3, MDA-MB-468, and HCC38 breast cancer cells
The breast CSCs enriched from the breast cancer cell lines have been previously shown to contain functional cancer stem cells with high CD44 and low CD24 expression and retain high tumorigenic activity when injected into the mammary fat pad of SCID mice [52,53,54,55,56]

Summary

Introduction

Breast cancer stem cells (CSCs) represent a subset of cancer cells with the capabilities of self-renewal and differentiation [1,2]. S1P can be released through specific transporters to act as a ligand for the family of G protein-coupled S1P receptors 1 to 5 (S1P1 to S1P5 ) and regulates a wide range of biological effects including transformation and cancer cell survival [24]. According to the sphingolipid rheostat model, the balance between these interconvertible sphingolipids, ceramide, sphingosine, and S1P, regulates cellular growth and survival in response to cellular and environmental stimuli [29,30,31,32,33]. SPHK is a critical regulator of this rheostat, as it produces the pro-growth and anti-apoptotic S1P and reduces levels of pro-apoptotic ceramide and sphingosine [26,30,34,35,36,37]. The inhibition of SPHK is likely to have an anti-cancer effect by producing apoptotic ceramide/sphingosine

Methods

Results

Conclusion