New Study Findings about Glycoprotein PTGDS
Glycoprotein prostaglandin D2 synthase (PTGDS) is a member of the lipocalcitonin superfamily that plays a dual role in prostaglandin metabolism and lipid transport. PTGDS is involved in various cellular processes including solid tumorigenesis, but its role in tumorigenesis is paradoxical, and the significance of PTGDS in hematologic malignancies is not clear. The aim of this new study was to investigate the expression and function of PTGDS in diffuse large b-cell lymphoma (DLBCL), especially the potential role of PTGDS inhibitor AT56 in lymphoma therapy. PTGDS is significantly highly expressed in DLBCL and is significantly associated with poor prognosis. Cell proliferation was promoted by PTGDS overexpression and rhPTGDS.
Diffuse large b-cell lymphoma (DLBCL) is a highly aggressive and heterogeneous tumor that is the most common form of non-Hodgkin's lymphoma. With the development of novel targeted therapies, most patients with DLBCL can be cured. However, 40–50% of patients with DLBCL still present with intractable or recurrent disease and eventually die of progressive disease. Therefore, the treatment of DLBCL also needs to find more new therapeutic targets.
Liposomal prostaglandin D synthase (L-PGDS), also known as PTGDS, is located on human chromosome 9 (9q34.2 to 34.3), a region of the lipocalin family. PTGDS, as a bifunctional protein, catalyzes the production and transport of lipophilic substances by PGD2. Oral administration of AT56, a selective inhibitor of PTGDS, competitively inhibited PTGDS activity (Km=14 μM). The glycoprotein PTGDS is synthesized and modified to be secreted extracellularly and soluble in body fluids. Recent studies have found that PTGDS is overexpressed in malignant melanoma, ovarian cancer, and hepatocellular adenoma. In contrast, other researchers found that PTGDS was downregulated and inhibited tumor progression in prostate tumors, lung tumors, and gastric cancer. In addition, recent studies have implicated PTGDS as a modulator of PPARγ, MAPK, and STAT3 pathways in the pathogenesis of hematologic malignancies. However, the role and mechanism of PTGDS in hematologic malignancies, especially DLBCL, have not been reported.
The aim of this study was to investigate the expression level of PTGDS in DLBCL and its mechanism of action. For the first time, enhanced PTGDS expression in DLBCL was found to be associated with poor treatment outcome and poor prognosis. In addition, in vitro, and in vivo studies showed that PTGDS inhibition markedly inhibited the progression of DLBCL through myh9-mediated Wnt β-catenin STAT3 signaling pathway. Inhibition of PTGDS enhanced drug sensitivity in DLBCL cells by inducing DNA damage. Low glycosylation of PTGDS induces nuclear translocation of DLBCL, prolongs half-life, and increases cell proliferation. In summary, this study reveals the carcinogenic role and mechanism of glycoprotein PTGDS in DLBCL, highlighting the potential therapeutic value of AT56 in the treatment of DLBCL.
Collectively, the results of this study are the first to demonstrate the high expression and oncogenic role of PTGDS in DLBCL and the efficacy of AT56 in the treatment of DLBCL. Notably, PTGDS inhibition showed a good anti-lymphoma effect both in vitro and in vivo through myh9-mediated Wnt β-catenin STAT3 signaling pathway. In addition, abnormal glycosylation of PTGDS may affect its intracellular location, half-life, and cancer induction. In conclusion, the results of this study indicate that glycoprotein PTGDS is a novel target for the treatment of DLBCL and highlight the potential of AT56 as a promising strategy for the treatment of DLBCL.
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