Implications of sphingosine kinase 1 expression level for the cellular sphingolipid rheostat: relevance as a marker for daunorubicin sensitivity of leukemia cells

Abstract

We recently reported increased sphingosine kinase 1 (SPHK1) and decreased neutral sphingomyelinase 2 (NSMase2) gene expression in myelodysplastic syndromes and acute leukemia. This alteration is supposed to change the cellular sphingolipid metabolites; however, positive correlations were observed between daunorubicin (DA)-IC50 and the SPHK1 message but not between DA-IC50 and NSMase2 messages, when 16 different leukemia cell lines were used to analyze the relationship between gene expressions and chemosensitivity against DA. Using two cell lines with either the highest or lowest SPHK1 expression, cellular ceramides and sphingosine 1-phosphate (S1P) were quantified by liquid chromatography/mass spectrometry. Increased ceramide was observed in DA-sensitive, but not in DA-resistant cell lines treated with low doses of DA. Upon DA treatment, S1P decreased more in the sensitive cell lines than in resistant cell lines. A SPHK inhibitor recovered the DA sensitivity of DA-resistant cells. The modulation of SPHK1 gene expression by either overexpression or using siRNA affected the DA sensitivity of representative cell lines. Results clearly show that SPHK1 is both a good marker to predict the DA sensitivity of leukemia cells and a potential therapeutic target for leukemia with high SPHK1 expression, and suggest that the sphingolipid rheostat plays a significant role in DA-induced cytotoxicity.

Sphingosine Kinase 2 Promotes Acute Lymphoblastic Leukemia by Enhancing MYC Expression

“…1). In the nucleus, SK2 binds directly to HDACs where locally produced S1P inhibits HDAC1 and 2, increasing acetylation of histone H3 on Lys 9 , H4 on Lys 5 , and H2B on Lys 12 (16). Gene expression of the cell-cycle inhibitor p21 and transcriptional regulator c-fos is subsequently increased, providing an explanation for the reported growth-inhibitory effects of SK2.…”

“…Overexpression of SK1 has indisputable tumor-promoting properties (2) and has been associated with poor survival in patients with solid tumor (3)(4)(5), resistance to imatinib in chronic myeloid leukemia (CML; refs. [6][7][8], and to daunorubicin in acute myeloid leukemia cells (9). In contrast, the role of SK2 in cancer is less clear.…”

The Apoptotic Mechanism of Action of the Sphingosine Kinase 1 Selective Inhibitor SKI-178 in Human Acute Myeloid Leukemia Cell Lines

“…Elevated expression of SphK1 is associated with numerous cancer types Sobue et al, 2008;Paugh et al, 2009;Knapp et al, 2010;Malavaud et al, 2010;Guan et al, 2011), and several lines of evidence link SphK1 deregulation with the progression of various hematologic malignancies (Van Brocklyn et al, 2005;Bonhoure et al, 2006;Bayerl et al, 2008;Paugh et al, 2008;Pitson et al, 2011). For example, overexpression of SphK1 has been shown to be an oncogenic event in acute erythroid leukemia progression (Le Scolan et al, 2005).…”

Roles of sphingosine 1-phosphate on tumorigenesis

“…Overexpression of SphK1 induces the transformation of NIH3T3 cells, based on the observation of colony formation on soft agar and the ability to form tumors in nude mice [57] . Furthermore, overexpression of SphK1 inhibits apoptosis and induces chemoresistance [12,58] . By comparing two different human prostate cancer cell lines, PC-3 and LNCaP, which are camptothecin (CPT)-resistance and -sensitive, respectively, Akao et al [59] have shown that PC-3 cells exhibit higher expression levels of SphK1, and also elevate S1P receptor expression, as compared with those in LNCaP cells.…”

“…Two distinct SphK isoforms have been identified, SphK1 and SphK2, both of which are responsible for conversion of sphingosine to S1P [70] . Recent, evidence has suggested that SphK1 possess many characteristics of oncogenes [12,55,57,58,71] . Furthermore, elevated expression of SphK1 is observed in multiple types of cancer, such as gastric, lung, brain, colon, kidney, and breast cancers, and associated with tumor grading as well as reduced patient survival [72][73][74][75][76][77][78][79][80] .…”