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

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.

Phosphoinositide‐dependent Kinase‐1 (PDPK1) regulates serum/glucocorticoid‐regulated Kinase 3 (SGK3) for prostate cancer cell survival

“…All cell protein lysates were harvested using ice-cold lysis buffer (1% NP-40, 1 mM DTT, protease inhibitors, and phosphatase inhibitor I and II cocktails in PBS) as previously described. 14,15 A total of 50μg protein was loaded for immunoblotting. Monoclonal antibodies against PDPK1 and β-actin were purchased from Santa Cruz Biotechnology, CA, USA.…”

The Importance of Sphingosine Kinase in Breast Cancer: A Potential for Breast Cancer Management

“…In a recent study, cytosolic S1P generated from SphK1 suppressed signal transducer and activator of transcription 1 (STAT1)-mediated interferon (IFN) signaling to allow excessive growth. STAT1 has shown tumor-suppressing properties, and when SphK1 was decreased, STAT1 signaling increased as well, leading to cell apoptosis [ 28 ]. Cytosolic S1P also has intracellular targets that induce inflammation.…”

“…This drug has been shown to inhibit the growth of breast cancer cells but with limited efficacy alone [ 35 ]. Studies have shown that in combination with doxorubicin or docetaxel (DTX), the dose needed for each drug was reduced, while the incidence of side effects of weight loss, liver toxicity, and lymphopenia also reduced [ 28 , 31 , 34 ]. The mechanism of FTY720 is well established and has been proven to reduce breast tumor size and growth in coordination with other modes of treatment for breast cancer.…”

“…The result indicates the need to test these compounds in vivo amply to see the overall effect. In a separate study, PF453 was proven to improve doxorubicin sensitivity in breast cancer cells, further demonstrating its efficacy [ 28 ]. SK1-I is another selective SphK1 inhibitor that has been shown to reduce angiogenesis and lymphangiogenesis [ 5 , 6 , 31 ].…”

Recent advances in the role of sphingosine 1‐phosphate in cancer

“…Conversely, knockdown of SK1 expression with siRNA increases apoptosis and reduces cell proliferation of both breast CSCs and non-CSCs. In addition, SK1-mediated suppression of STAT1 was identified as a mechanism that promotes cancer cell survival, with STAT1 and IFN signalling being novel regulatory targets of SK1 [66]. Overexpression of SK1 also enhances stemness and self-renewal of ovarian cancer cells, via a SOX2-dependent mechanism, thereby enhancing tumour clonogenicity.…”