The Relationship of Sphingosine Kinase 1 With Pyroptosis Provides a New Strategy for Tumor Therapy

Abstract

Sphingosine kinase 1 (SPHK1) is a crucial molecule that catalyzes sphingosine to synthesize sphingosine-1-phosphate (S1P), facilitating cell survival signaling. Pyroptosis is a perplexing inflammatory mode of cell death primarily triggered by caspase-1, evoked by the NLRP3 inflammasome. Sphingosine is identified as a danger-associated molecular pattern (DAMP), which activates the NLRP3 inflammasome assembly and induces the pyroptosis. It has been demonstrated that macrophages play a pro-tumorigenic role and are closely associated with tumor progression. Attenuation of SPHK1 activity contributes significantly to macrophage pyroptosis and tumor inhibition. Calcium and integrin-binding protein 1 (CIB1) plays an important role in the translocation of SPHK1 from the cytoplasm to the plasma membrane, whereas CIB2 blocks the subcellular trafficking of SPHK1. Therefore, knockout of CIB1 or over-expression of CIB2 will result in sphingosine accumulation and contribute significantly to cancer treatment by several approaches. First, it directly provokes cancer cell apoptosis or triggers robust anti-tumor immunity by pyroptosis-induced inflammation. Second, it could restrain SPHK1 translocation from the cytoplasm to the plasma membrane and further pyroptosis, which not only drive M2 macrophages death but also facilitate tumor microenvironment inflammation as well as the further release of sphingosine from damaged macrophages. The perspective might provide novel insight into the association between SPHK1 and pyroptosis and suggest the potential target for cancer therapy.

Keywords: calcium and integrin-binding protein 1; cancer; pyroptosis; sphingosine-1-phosphate; spingosine kinase 1.

Figure 1

Ceramide, primarily located in the endoplasmic reticulum membrane, generates sphingosine (Sph) by ceramidase. Both ceramide and Sph could contribute to cell apoptosis. On the one hand, Sph migrates to the cytomembrane from the endoplasmic reticulum (ER) membrane and produces sphingosine-1-phosphate (S1P) by sphingosine kinase 1 (SPHK1). In contrast to the apoptotic effect of Sph, S1P could facilitate cell survival signaling. On the other hand, SPHK1 subcellular localization was regulated by calcium and integrin-binding protein 1 (CIB1) and CIB2. It is believed that the translocation of SPHK1 from the cytoplasm to the cytomembrane is dependent on CIB1, whereas CIB2 competes with CIB1 to binds to SPHK1, resulting in the cytoplasm retention of SPHK1 and the inhibition of its enzymatic activity. Additionally, the accumulation of Sph in ER acts as DAMPs to activate NLRP3 and the oligomeric RLRP3 inflammasome, further causing caspase-1 homo activation and activated caspase-1 cleave gasdermin D to form N-terminal and pro-IL-1β/pro-IL-18 to yield IL-1β/IL-18, respectively. Then N-terminal of gasdermin D will form the channels in the plasma membrane causing massive leakage of cytosolic contents including IL-1β and IL-18, which leads to tumor microenvironment inflammation in that IL-1β can activate primary T cells and memory T cells, IL-18 can promote interferon (IFN)-γ production in TH1 cells, NK cells and cytotoxic T cells, boost the development of TH2 cells, and improve local inflammation response.