SPHK1 regulates proliferation and survival responses in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is characterized by unique aggressive behavior and lack of targeted therapies. Among the various molecular subtypes of breast cancer, it was observed that TNBCs express elevated levels of sphingosine kinase 1 (SPHK1) compared to other breast tumor subtypes. High levels of SPHK1 gene expression correlated with poor overall and progression- free survival, as well as poor response to Doxorubicin-based treatment. Inhibition of SPHK1 was found to attenuate ERK1/2 and AKT signaling and reduce growth of TNBC cells in vitro and in a xenograft SCID mouse model. Moreover, SPHK1 inhibition by siRNA knockdown or treatment with SKI-5C sensitizes TNBCs to chemotherapeutic drugs. Our findings suggest that SPHK1 inhibition, which effectively counteracts oncogenic signaling through ERK1/2 and AKT pathways, is a potentially important anti-tumor strategy in TNBC. A combination of SPHK1 inhibitors with chemotherapeutic agents may be effective against this aggressive subtype of breast cancer.

Hepatitis B virus X protein promotes human hepatoma cell growth via upregulation of transcription factor AP2α and sphingosine kinase 1

“…Functionally, we demonstrated that SPHK1 siRNA remarkably inhibited the growth of hepatoma mediated by HBx in vitro and in vivo. Our data are consistent with the reports that SPHK1 is able to promote tumor cell proliferation [17,43] . Therefore, HBx modulates SPHK1 via upregulating transcriptional factor AP2α in promotion of hepatoma cell growth.…”

“…Substantial evidence has suggested that HBx displays crucial functions in the pathogenesis of HCC [2,27] . It has been reported that SPHK1 plays an important role in the regulation of fundamental biological processes and tumorigenesis [17,[28][29][30] . Therefore, we are interested in whether SPHK1 is involved in HBx-induced hepatocarcinogenesis.…”

“…Sphingosine kinase 1 promotes tumor cell migration and invasion via the S1P/EDG1 axis in HCC [16] . SPHK1 regulates proliferation and survival responses in triple-negative breast cancer [17] . Furthermore, inhibition of SPHK1 can suppress the migration and proliferation of ovarian cancer and hepatocellular carcinoma cells [18][19][20] .…”

Recent advances in the development of sphingosine kinase inhibitors

“…In U937 cells, SK1-5c was shown to have only modest inhibitory effects on cell proliferation [103], but substantially reduced viability of colon cancer cells with a concomitant reduction in Akt signalling [105]. SK1-5c reduced proliferation and in vitro colony formation and induced apoptosis in triple-negative MDA-MB-231 and ER-positive MCF-7 breast cancer cell lines [106], and attenuated tumour growth in a mouse MDA-MB-231 xenograft model [106] (Table 2). A previous study used SK1-5c in vivo where it exerted similar effects to SKI-II in reducing S1P receptor activation in a mouse model of renal ischemia-reperfusion injury [107].…”

“…A previous study used SK1-5c in vivo where it exerted similar effects to SKI-II in reducing S1P receptor activation in a mouse model of renal ischemia-reperfusion injury [107]. SK1-5c has also been used to effectively chemo-sensitise MDA-MB-231 breast cancer cells [106] and a panel of colon cancer cell lines [105], a result that was pheno-copied by siRNA knockdown of SK1 [105,106]. These results suggest that SK1-5c may be a selective SK1 inhibitor; however, further studies characterizing its effects upon other lipid and protein kinases and other sphingolipid metabolizing enzymes are required.…”