Abstract
Glycoprotein prostaglandin D2 synthase (PTGDS) is a member of the lipocalin superfamily and plays dual roles in prostaglandins metabolism and lipid transport. PTGDS has been involved in various cellular processes including the tumorigenesis of solid tumors, yet its role in carcinogenesis is contradictory and the significance of PTGDS in hematological malignancies is ill-defined. Here, we aimed to explore the expression and function of PTGDS in diffuse large B-cell lymphoma (DLBCL), especially the potential role of PTGDS inhibitor, AT56, in lymphoma therapy. Remarkable high expression of PTGDS was found in DLBCL, which was significantly correlated with poor prognosis. PTGDS overexpression and rhPTGDS were found to promote cell proliferation. Besides, in vitro and in vivo studies indicated that PTGDS knockdown and AT56 treatment exerted an anti-tumor effect by regulating cell viability, proliferation, apoptosis, cell cycle, and invasion, and enhanced the drug sensitivity to adriamycin and bendamustine through promoting DNA damage. Moreover, the co-immunoprecipitation-based mass spectrum identified the interaction between PTGDS and MYH9, which was found to promote DLBCL progression. PTGDS inhibition led to reduced expression of MYH9, and then declined activation of the Wnt-β-catenin-STAT3 pathway through influencing the ubiquitination and degradation of GSK3-β in DLBCL. The rescue experiment demonstrated that PTGDS exerted an oncogenic role through regulating MYH9 and then the Wnt-β-catenin-STAT3 pathway. Based on point mutation of glycosylation sites, we confirmed the N-glycosylation of PTGDS in Asn51 and Asn78 and found that abnormal glycosylation of PTGDS resulted in its nuclear translocation, prolonged half-life, and enhanced cell proliferation. Collectively, our findings identified for the first time that glycoprotein PTGDS promoted tumorigenesis of DLBCL through MYH9-mediated regulation of Wnt-β-catenin-STAT3 signaling, and highlighted the potential role of AT56 as a novel therapeutic strategy for DLBCL treatment.
Highlights
Diffuse large B-cell lymphoma (DLBCL), a highly aggressive and heterogeneous tumor, is the most common form of non-Hodgkin lymphoma [1]
In progression To elucidate the expression level of prostaglandin D2 synthase (PTGDS) in DLBCL, analysis based addition, the expression of Cyclin D1 and CDK2 was reduced by PTGDS knockdown (Fig. 2M), which promoted the transformation on IHC staining showed that PTGDS was upregulated in DLBCL
PTGDS was upregulated in human DLBCL and its high expression was correlated with inferior prognosis of DLBCL patients, especially non-GCB subtype
Summary
Diffuse large B-cell lymphoma (DLBCL), a highly aggressive and heterogeneous tumor, is the most common form of non-Hodgkin lymphoma [1]. With the development of novel targeted therapy, the majority of DLBCL patients could be cured. 40–50% of DLBCL patients still presented refractory or relapse and eventually died of disease progression [2]. Identifying more novel therapeutic targets is still needed for DLBCL treatment [3]. Lipocalin prostaglandin D synthetase (L-PGDS), known as PTGDS, is located in human chromosome 9 (9q34.2~34.3), the region of the lipocalin family [4, 5]. PTGDS acts as a bifunctional protein that catalyzes PGD2 production and transports lipophilic substances [5]. Glycoprotein PTGDS could be secreted outside the cell and dissolved in body fluid
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
