S1PR1/S1PR3-YAP signaling and S1P-ALOX15 signaling contribute to an aggressive behavior in obesity-lymphoma

Abstract

Background Excess body weight has been found to associate with an increased risk of lymphomas and some metabolic pathways are currently recognized in lymphomagenesis. Bioactive lipid metabolites such as sphingosine-1-phosphate (S1P) have been proposed to play an important role linking obesity and lymphomas. However, the underlying mechanism(s) of S1P signaling in obesity-lymphomagenesis have not been well addressed. Methods The gene expression of sphingosine kinase (SPHK), lymphoma prognosis, and S1P production were analyzed using Gene Expression Omnibus (GEO) and human lymphoma tissue array. Obesity-lymphoma mouse models and lymphoma cell lines were used to investigate the S1P/SPHK-YAP axis contributing to obesity-lymphomagenesis. By using the mouse models and a monocyte cell line, S1P-mediated polarization of macrophages in the tumor microenvironment were investigated. Results In human study, up-regulated S1P/SPHK1 was found in human lymphomas, while obesity negatively impacted progression-free survival and overall survival in lymphoma patients. In animal study, obesity-lymphoma mice showed an aggressive tumor growth pattern. Both in vivo and in vitro data suggested the existence of S1P-YAP axis in lymphoma cells, while the S1P-ALOX15 signaling mediated macrophage polarization towards TAMs exacerbated the lymphomagenesis. In addition, treatment with resveratrol in obesity-lymphoma mice showed profound effects of anti-lymphomagenesis, via down-regulating S1P-YAP axis and modulating polarization of macrophages. Conclusion S1P/S1PR initiated the feedback loops, whereby S1P-S1PR1/S1PR3-YAP signaling mediated lymphomagenesis contributing to tumor aggressive growth, while S1P-ALOX15 signaling mediated TAMs contributing to immunosuppressive microenvironment in obesity-lymphoma. S1P-targeted therapy could be potentially effective and immune-enhancive against obesity-lymphomagenesis. Graphical Abstract

Role for CCN1 in lysophosphatidic acid response in PC‐3 human prostate cancer cells

“…72 PC-3 cells express S1P1, S1P2, and S1P3, 8 all of which can activate YAP. 71,73,74 Thus, it is likely that both LPA and S1P induce CCN proteins via a YAP-dependent pathway in PC-3 cells. We report for the first time, that 18:1-LPA and 18:0 LPA have differential effects on CCN1 induction in prostate cancer cells, with 18:1-LPA being more efficacious.…”

“… 72 PC‐3 cells express S1P1, S1P2, and S1P3, 8 all of which can activate YAP. 71 , 73 , 74 Thus, it is likely that both LPA and S1P induce CCN proteins via a YAP‐dependent pathway in PC‐3 cells.…”

Lipoxygenases at the Intersection of Infection and Carcinogenesis

“…In detailing the mechanism of sphingosine-1-phosphate (S1P) in obesitylymphomagenesis, a recent study demonstrated that up-regulated S1P-S1P receptors 1/2-YAP signaling mediates the aggressive nature of obesity-lymphoma by inducing cell proliferation and migration. More importantly, S1P-ALOX15 signaling mediates polarization of macrophages towards tumor-associated macrophages, establishing an immunosuppressive microenvironment [209]. In a separate study, both ALOX15 and ALOX15B isoforms were identified in normal mammary epithelial cells as well as in vascular endothelial cells, and the expression of both isoforms was considerably diminished in breast tumor tissues [143].…”

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy

“…Aside from normal cell types, S1PR3 is highly expressed in various cancer cells and was shown to stimulate cancer progression [ 21 , 153 , 168 ]. It is common to observe the co-expression of different S1P receptors, especially presence of S1PR1 and S1PR3 within one cell type which may indicate cooperation of signaling among the receptors [ 174 ]. In comparison to S1PR1 and S1PR3 effects, S1PR4 was found to be growth-inhibitory in some immune cells [ 175 ], while its role in the lymphocyte trafficking and expansion was extensively discussed [ 169 ].…”