S1PR1 is an effective target to block STAT3 signaling in activated B cell–like diffuse large B-cell lymphoma
-
- Yong Liu
- Departments of Cancer Immunotherapeutics and Tumor Immunology,
-
- Jiehui Deng
- Departments of Cancer Immunotherapeutics and Tumor Immunology,
-
- Lin Wang
- Departments of Cancer Immunotherapeutics and Tumor Immunology,
-
- Heehyoung Lee
- Departments of Cancer Immunotherapeutics and Tumor Immunology,
-
- Brian Armstrong
- Neurosciences, and
-
- Anna Scuto
- Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA; and
-
- Claudia Kowolik
- Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA; and
-
- Lawrence M. Weiss
- Departments of Pathology and
-
- Stephen Forman
- Hematology/Hematopoietic Cell Transplantation, City of Hope, Duarte, CA
-
- Hua Yu
- Departments of Cancer Immunotherapeutics and Tumor Immunology,
書誌事項
- 公開日
- 2012-08-16
- DOI
-
- 10.1182/blood-2011-12-399030
- 公開者
- American Society of Hematology
この論文をさがす
説明
<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>
収録刊行物
-
- Blood
-
Blood 120 (7), 1458-1465, 2012-08-16
American Society of Hematology