Targeting SphK1 as a New Strategy against Cancer

Abstract

Sphingolipid metabolites have emerged as critical players in a number of fundamental biological processes. Among them, sphingosine-1-phosphate (S1P) promotes cell survival and proliferation, in contrast to ceramide and sphingosine, which induce cell growth arrest and apoptosis. These sphingolipids with opposing functions are interconvertible inside cells, suggesting that a finely tuned balance between them can determine cell fate. Sphingosine kinases (SphKs), which catalyze the phosphorylation of sphingosine to S1P, are critical regulators of this balance. Of the two identified SphKs, sphingosine kinase type 1 (SphK1) has been shown to regulate various processes important for cancer progression and will be the focus of this review, since much less is known of biological functions of SphK2, especially in cancer. SphK1 is overexpressed in various types of cancers and upregulation of SphK1 has been associated with tumor angiogenesis and resistance to radiation and chemotherapy. Many growth factors, through their tyrosine kinase receptors (RTKs), stimulate SphK1 leading to a rapid increase in S1P. This S1P in turn can activate S1P receptors and their downstream signaling. Conversely, activation of S1P receptors can induce transactivation of various RTKs. Thus, SphK1 may play important roles in S1P receptor RTK amplification loops. Here we review the role of SphK1 in tumorigenesis, hormonal therapy, chemotherapy resistance, and as a prognostic marker. We will also review studies on the effects of SphK inhibitors in cells in vitro and in animals in vivo and in some clinical trials and highlight the potential of SphK1 as a new target for cancer therapeutics.

Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro

“…10 Therefore, a combination therapy based on a SphK1 inhibitor and radiation could provide a useful strategy for the treatment of therapeutic-resistant cancers. 24 Here we report that targeting SphK1 with FTY720 potentiated radiation-induced suppression of cell proliferation and induction of apoptosis. Our findings are in agreement with a recent work by Pchekectski et al 9 showing that FTY720 acts as a radiosensitizer on prostate cancer cell lines.…”

Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts

“…Although both enzymes catalyze the same reaction and produce S1P, the physiological or pathophysiological functions of the two subtypes and variants are presently still unclear. Many studies have addressed the functions of SK-1 and there is a broad consent on its key function in cell proliferation and migration (Shida et al, 2008;Pyne and Pyne, 2010). This is further supported by studies showing an upregulation of SK-1 mRNA in several cancer types (French et al, 2003(French et al, , 2006 for review see Pyne and Pyne, 2010).…”

Review of the Molecular Pathogenesis of Osteosarcoma

“…The lipid kinase sphingosine kinase 1 (SphK1) catalyzes the phosphorylation of sphingosine to sphingosine-1-phosphate (S1P) ( Shida et al, 2008;Vadas et al, 2008). In vivo and in vitro studies have proven that SphK1 is associated with cancer cell survival, proliferation, transformation, and prevention of apoptosis, the chemotherapy resistance and angiogenesis (Shida et al, 2008;Vadas et al, 2008).…”

“…In vivo and in vitro studies have proven that SphK1 is associated with cancer cell survival, proliferation, transformation, and prevention of apoptosis, the chemotherapy resistance and angiogenesis (Shida et al, 2008;Vadas et al, 2008). Evidence from clinical samples demonstrates that SphK1 is over-expressed in many tumor types and that inhibitors of SphK1 may sensitize tumors to chemotherapeutic agents (Shida et al, 2008;Vadas et al, 2008). SphK1 is over-expressed in multiple clinical OSA tissues.…”