Sphingosine Kinase 1 Promotes Malignant Progression in Colon Cancer and Independently Predicts Survival of Patients With Colon Cancer by Competing Risk Approach in South Asian Population

Abstract

Objectives:Sphingosine kinase 1 (SphK1) phosphorylates the membrane sphingolipid, sphingosine, to sphingosine-1-phosphate (S1P), an oncogenic mediator, which drives tumor cell growth and survival. Although SphK1 has gained increasing prominence as an oncogenic determinant in several cancers, its potential as a therapeutic target in colon cancer remains uncertain. We investigated the clinical relevance of SphK1 expression in colon cancer as well as its inhibitory effects in vitro.Methods:SphK1 expression in human colon tumor tissues was determined by immunohistochemistry and its clinicopathological significance was ascertained in 303 colon cancer cases. The effects of SphK1 inhibition on colon cancer cell viability and the phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway were investigated using a SphK1-selective inhibitor—compound 5c (5c). The cytotoxicity of a novel combination using SphK1 inhibition with the chemotherapeutic drug, 5-fluorouracil (5-FU), was also determined.Results:High SphK1 expression correlated with advanced tumor stages (AJCC classification). Using a competing risk analysis model to take into account disease recurrence, we found that SphK1 is a significant independent predictor for mortality in colon cancer patients. In vitro, the inhibition of SphK1 induced cell death in colon cancer cell lines and attenuated the serum-dependent PI3K/Akt signaling. Inhibition of SphK1 also enhanced the sensitivity of colon cancer cells to 5-FU.Conclusion:Our findings highlight the impact of SphK1 in colon cancer progression and patient survival, and provide evidence supportive of further development in combination strategies that incorporate SphK1 inhibition with current chemotherapeutic agents to improve colon cancer outcomes.

Predictive Value of Sphingosine Kinase 1 Expression in Papillary Thyroid Carcinoma

“…These findings are consistent with our data showing that high sphingosine kinase 1 expression is associated with aggressive oncogenic behavior including tumor multiplicity, extrathyroidal extension, and lymph node metastasis. Our results are also consistent with studies demonstrating an association between elevated sphingosine kinase 1 expression and aggressive oncogenic behavior such as larger tumor size, deeper invasion depth, advanced stage, worse histological differentiation, higher invasiveness, and chemotherapeutic resistance in cancers of the cervix (14), head and neck (37), thyroid (31), salivary duct (32), esophagus (38), colon/rectum (39), and bladder (40).…”

Recent advances in the development of sphingosine kinase inhibitors

“…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.…”

“…SK1-5c did not inhibit PKC at concentrations below 100 μM [103] but its selectivity over other enzymes remains untested. 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).…”

Visualizing red blood cell sickling and the effects of inhibition of sphingosine kinase 1 using soft X-ray tomography

“…Previous work has demonstrated that sphingosine kinase 1 (Sphk1) inhibitors significantly decreased sickling RBCs in mice (Zhang et al, 2014) and compound 5C has been shown to specifically inhibit Sphk1 Tan et al, 2014;Wong et al, 2009). When comparing the staged sickle RBCs under hypoxia conditions, without and with treatment (Fig.…”