Abstract
AbstractProstaglandin D2 (PGD2), an arachidonic acid metabolite, has been implicated in allergic responses, parasitic infection and tumor development. The biological functions and molecular mechanisms of PGD2 in diffuse large B-cell lymphoma (DLBCL) are still undefined. In this study, we firstly found the high concentration of serum PGD2 and low expression of PGD2 receptor CRTH2 in DLBCL, which were associated with clinical features and prognosis of DLBCL patients. Interestingly, different concentration of PGD2 displayed divergent effects on DLBCL progression. Low-concentration PGD2 promoted cell growth through binding to CRTH2 while high-concentration PGD2 inhibited it via regulating cell proliferation, apoptosis, cell cycle, and invasion. Besides, high-concentration PGD2 could induce ROS-mediated DNA damage and enhance the cytotoxicity of adriamycin, bendamustine and venetoclax. Furthermore, HDAC inhibitors, vorinostat (SAHA) and panobinostat (LBH589) regulated CRTH2 expression and PGD2 production, and CRTH2 inhibitor AZD1981 and high-concentration PGD2 enhanced their anti-tumor effects in DLBCL. Altogether, our findings demonstrated PGD2 and CRTH2 as novel prognostic biomarkers and therapeutic targets in DLBCL, and highlighted the potency of high-concentration PGD2 as a promising therapeutic strategy for DLBCL patients.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology
Reference69 articles.
1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer J clinicians 2021;71:209–49.
2. Chu Y, Zhou X, Wang X. Antibody-drug conjugates for the treatment of lymphoma: clinical advances and latest progress. J Hematol Oncol. 2021;14:88.
3. Sarkozy C, Sehn LH. Management of relapsed/refractory DLBCL. Best Pr Res Clin Haematol. 2018;31:209–16.
4. Matthews JM, Bhatt S, Patricelli MP, Nomanbhoy TK, Jiang X, Natkunam Y, et al. Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma. Blood 2016;128:239–48.
5. Cheson BD. Predicting the future for DLBCL. Blood 2020;135:1308–9.