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.

Detection of immune-related cells and genes in the glioma tumor microenvironment from the CGGA database using bioinformatics strategies

“…In the present research, we discovered that two types of immune cells, macrophages M0 and monocytes, are closely associated with the survival of patients with glioma. During immune editing, immune cells have the function of withdrawing and evoking tumorigenic responses [26]. Macrophages are the most abundant cells in the tumor microenvironment and are highly plastic, making them perform multiple functions in the tumor microenvironment [27].…”

The dance of macrophage death: the interplay between the inevitable and the microenvironment

“…The concept was based on the findings that sphingosine, the substrate for SPHK1, can derive from cancer cells and act as a DAMP. Its accumulation can lead to pyroptosis in tumor-associated macrophages and further induction of anti-tumor immune response ( 228 ). While no publication delves deeper into and supports their hypothesis, there is a study focusing on related molecules.…”

“…Targeting TAMs pyroptosis may diminish the number of often pro-tumorigenic macrophages and promote antitumor immunity simultaneously. Several studies have suggested that the induction of macrophage pyroptosis can stimulate an anticancer immune response, thereby being favorable ( 217 , 228 , 231 ). Okondo et al.…”

NLRP3 Inflammasome in Relation to Glucose and Lipid Metabolism, and Insulin Resistance in Diabetes and Pre-Diabetes

“…Nod-like receptor protein 3 (NLRP3) inflammasome is a multi-protein complex composed of the core member (NLRP3), apoptosis-associated spot-like protein (ASC), and Caspase-1 [6] [7]. Chronic inflammatory responses mediated by NLRP3 inflammasome and related factors play an important role in the progression of diabetes [5].…”