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A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
Published on: June 8, 2022
S1PR1 is an effective target to block STAT3 signaling in activated B cell-like diffuse large B-cell lymphoma
Yong Liu1, Jiehui Deng, Lin Wang
1Departments of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
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.
Insights
Targeting sphingosine-1-phosphate receptor 1 (S1PR1) may offer a new therapy for activated B-cell-like diffuse large B-cell lymphoma. Inhibiting S1PR1 down-regulates STAT3 activity, hindering lymphoma tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Signal transducer and activator of transcription 3 (STAT3) is crucial in human cancer progression, including B-cell lymphomas.
- STAT3, a transcription factor without enzymatic activity, presents challenges for small-molecule drug targeting.
- The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) is often less responsive to current therapies.
Purpose of the Study:
- To investigate the role of sphingosine-1-phosphate receptor 1 (S1PR1) in ABC-DLBCL.
- To explore the therapeutic potential of targeting S1PR1 in ABC-DLBCL.
Main Methods:
- Analysis of STAT3 and S1PR1 expression in patient-derived ABC-DLBCL samples.
- Inhibition of S1PR1 using short hairpin RNA (shRNA) or FTY720 (a sphingosine-1-phosphate antagonist).
- Assessment of STAT3 activity, downstream gene expression, and lymphoma cell growth in vitro and in vivo.
Main Results:
- Persistent activated STAT3 colocalized with elevated S1PR1 expression in ABC-DLBCL tumor cells.
- S1PR1 inhibition affected STAT3 downstream genes involved in tumor cell survival, proliferation, invasion, and immunosuppression.
- S1PR1 inhibition, via shRNA or FTY720, down-regulated STAT3 activity and inhibited lymphoma cell growth in vitro and in vivo.
Conclusions:
- Targeting the S1P/S1PR1 pathway presents a potential therapeutic strategy for ABC-DLBCL.
- FTY720, a clinically available drug, could be repurposed for treating this lymphoma subtype.
- This approach offers a promising new modality for a challenging subset of lymphoma.
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