Targeting the Sphingosine Kinase/Sphingosine-1-Phosphate Signaling Axis in Drug Discovery for Cancer Therapy

Abstract

Sphingolipid metabolites have emerged as critical players in the regulation of various physiological processes. Ceramide and sphingosine induce cell growth arrest and apoptosis, whereas sphingosine-1-phosphate (S1P) promotes cell proliferation and survival. Here, we present an overview of sphingolipid metabolism and the compartmentalization of various sphingolipid metabolites. In addition, the sphingolipid rheostat, a fine metabolic balance between ceramide and S1P, is discussed. Sphingosine kinase (SphK) catalyzes the synthesis of S1P from sphingosine and modulates several cellular processes and is found to be essentially involved in various pathophysiological conditions. The regulation and biological functions of SphK isoforms are discussed. The functions of S1P, along with its receptors, are further highlighted. The up-regulation of SphK is observed in various cancer types and is also linked to radio- and chemoresistance and poor prognosis in cancer patients. Implications of the SphK/S1P signaling axis in human pathologies and its inhibition are discussed in detail. Overall, this review highlights current findings on the SphK/S1P signaling axis from multiple angles, including their functional role, mechanism of activation, involvement in various human malignancies, and inhibitor molecules that may be used in cancer therapy.

Keywords: cancer therapy; drug design and discovery; kinase inhibitors; sphingosine kinase; sphingosine metabolism.

Figure 1

Sphingolipid metabolism and compartmentalization. Three significant mechanisms for ceramide generation are illustrated. Ceramide is synthesized via s “de novo pathway” in the ER from where it is transported to the Golgi bodies through CERT and serves as a substrate for the synthesis of complex glycosphingolipids (GLSL) and sphingomyelin (SM). GLSL and SM are transported to the plasma membrane through vesicular transport. In another mechanism; ceramide can be generated by the action of neutral or acidic SMases (“SMase pathway”) in the plasma membrane. Finally, in the “salvage pathway”, ceramide is synthesized from sphingosine released from the lysosome by the catalytic action of CERS. (SPT, Serine palmitoyltransferase; CERS, Ceramide synthase; CERK, Ceramide kinase; CPP, Ceramide-1-phosphate phosphatase; SMS, Sphingomyelin synthase; SMase, Sphingomyelinase; ACER, ceramidase in Golgi bodies; ASAH, ceramidase in lysosomes; SK, sphingosine kinase; SPP, Sphingosine-1-phosphate phosphatase; SPL, S1P lyase) (Figure is adapted from reference [18]).

Figure 2

Functional roles of SphKs and S1P in cells. Upon ERK1/2 mediated phosphorylation/activation in the presence of various agonist (such as TNFα, cytokines and diverse growth factors), SphK1 is translocated to plasma membrane from cytoplasm and interact with calcium-myristoyl switch protein 1 (C1B1). This facilitates the phosphorylation of sphingosine to generate S1P, which can either be secreted out or interacts with intracellular targets (such as TRAF2) to elicit its functions. Once secreted out of the cell, S1P binds to the S1P receptor (S1PR) embedded in the plasma membrane and activates various downstream signaling pathways that control cell survival, proliferation, and migration. In the nucleus, SphK2 catalyzes the phosphorylation of sphingosine to generate S1P that inhibits the activity of histone deacetylases (HDAC1/2) and regulates gene expression. S1P also binds to human telomerase reverse transcriptase (hTERT) at the nuclear periphery in human and mouse fibroblasts that inhibits its interaction with makorin ring finger protein 1 (MKRN1) and promotes telomerase stability. S1P is also produced in the mitochondria by the action of SphK2.

Figure 3

Role of S1P receptors in cancer. Once exported outside the cell, S1P binds and activates S1PR_1-5 that further stimulates receptor-bound G-proteins (G_12/13, G_q, G_i). Subsequently, the activated G-proteins turn on diverse downstream signaling pathways that play a crucial role in tumorigenesis. A cross-talk between various downstream targets of different S1PRs regulating cancer progression is evident (Adapted from [93]).

Figure 4

Schematic representation showing the role of the SphK1/S1P axis in breast cancer progression and metastasis. S1PR1 and S1PR3 are the two S1P receptors playing a major role in breast cancer development which initiate a cascade via activating STAT3, various RTKs, Notch, p38MAPK, ERK1/2, and AKT/PI3K cumulatively resulting in breast cancer metastasis.

Figure 5

SphK1 and S1P signaling in colorectal carcinogenesis and progression. S1P produced by SphK1 results in the activation of NF-κB and IL-6/STAT3/AKT pathway intracellularly that prevents apoptosis, ultimately leading to cell transformation and angiogenesis in colitis-associated cancer and chronic intestinal inflammation, whereas signaling from S1PR1 maintains persistently activated STAT3 and up regulation of SphK, which contributes to the overall increase in S1P pool. Also, SphK inhibitors, SKI-II and FTY720 are known to suppress the progression of colon cancer.

Figure 6

Compounds targeting SphK/S1P/S1PR signaling cascade and mediating anticancer activity. The up-regulation of SphK is observed in various tumor types and is linked to cancer progression. Enhanced SphK activity leads to elevated intracellular levels of S1P and subsequent over-activation and functioning of S1PRs, finally resulting in a marked increase in cell proliferation, angiogenesis, and metastasis. Several compounds (SKIs) that target and inhibit SphK/S1P/S1PR signaling axis are shown. They cause the tipping of sphingolipid rheostat towards the pro-apoptotic ceramide side leading to inhibition of cancer progression. Thus, SKIs can act as potential cancer therapeutics after proper evaluation and validation in efficacy and safety.