title: S1PR1 is an effective target to block STAT3 signaling in activated B cell-like diffuse large B-cell lymphoma.
abstract: STAT3 plays a crucial role in promoting progression of human cancers, including several types of B-cell lymphoma. However, as a transcription factor lacking its own enzymatic activity, STAT3 remains difficult to target with small-molecule drugs in the clinic. Here we demonstrate that persistent activated STAT3 colocalizes with elevated expression of S1PR1, a G-protein-coupled receptor for sphingosine-1-phosphate (S1P), in the tumor cells of the activated B cell-like subtype of diffuse large B-cell lymphoma patient specimens. Inhibition of S1PR1 expression by shRNA in the lymphoma cells validates that blocking S1PR1 affects expression of STAT3 downstream genes critically involved in tumor cell survival, proliferation, tumor invasion, and/or immunosuppression. Using S1PR1 shRNA, or FTY720, an antagonist of S1P that is in the clinic for other indications, we show that inhibiting S1PR1 expression down-regulates STAT3 activity and causes growth inhibition of the lymphoma tumor cells in vitro and in vivo. Our results suggest that targeting S1P/S1PR1 using a clinically relevant and available drug or other approaches is potentially an effective new therapeutic modality for treating the activated B cell-like subtype of diffuse large B-cell lymphoma, a subset of lymphoma that is less responsive to current available therapies.
authors: Departments of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors: Yong
authors: Y
authors: Liu
authors: Jiehui
authors: J
authors: Deng
authors: Lin
authors: L
authors: Wang
authors: Heehyoung
authors: H
authors: Lee
authors: Brian
authors: B
authors: Armstrong
authors: Anna
authors: A
authors: Scuto
authors: Claudia
authors: C
authors: Kowolik
authors: Lawrence M
authors: LM
authors: Weiss
authors: Stephen
authors: S
authors: Forman
authors: Hua
authors: H
authors: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D011409:Propylene Glycols / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D011409:Propylene Glycols; D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; C556330:S1pr1 protein, mouse; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C494087:Stat3 protein, mouse; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine