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 celllike subtype of diffuse large B-cell lymphoma, a subset of lymphoma that is less responsive to current available therapies. (Blood. 2012;120(7):1458-1465) IntroductionDiffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, including subtypes with diverse origins and gene expression profiles. [1][2][3][4][5][6] One of the most aggressive histologies, activated B cell-like DLBCL (ABC-DLBCL) remains a challenge for effective therapy, despite extensive studies of morphology and gene expression patterns. [5][6][7][8][9][10] In vitro, cells of the ABC-DLBCL subtype have gene expression patterns similar to those of activated peripheral blood B cells, such as the NF-B downstream genes IRF4, CD44, and cyclin D2. 11 At the same time, these tumor cells also secrete IL-6 and IL-10 through autocrine/paracrine pathways. 12 Consistent with this, the constitutive activation of NF-B and Janus kinase (JAK) is shown to promote tumorigenicity of malignant B-cell lymphoma, including ABC-DLBCL. 13 One promising candidate for ABC-DLBCL targeted therapy is signal transducer and activator of transcription 3 (STAT3). STAT3 is a transcriptional factor that is constitutively activated in many types of cancer, contributing to tumor progression via several mechanisms. 14-20 STAT3 is shown to be activated in the ABC-DLBCL subtype. 20,21 Approximately one-third of ABC-DLBCL patients have gain-of-function mutations in the adaptor protein MYD88, which leads to JAK and STAT3 activation, as well as IL-6 and IL-10 secretion. 13 IL-6 and IL-10 secretion can further increase STAT3 activation levels within tumor cells via an autocrine feedback loop. 14 IL-6-activated STAT3 is crucial for survival of several types of cancer cells, including multiple myeloma, a plasmacytic B-cell malignancy. 14,22 IL-10 is also important for STAT3-mediated immune suppre...

Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs

“…This finding is consistent with the observation of others that S1P and STAT3 signaling is linked in a coactivating pathway, in which S1P acts through S1PR1 to activate JAK2/STAT3. STAT3 is a transcriptional activator of IL-6 and S1PR1 (15,40). Whereas the prior studies used artificial expression systems to demonstrate this interaction, we have found that treatment of WT MEFs promotes JAK2 activation in a manner that requires S1P export via SPNS2 and extracellular S1PR1 signaling.…”

Export of sphingosine-1-phosphate and cancer progression

“…It is of great importance to progression ( 81 ). This S1PR1-STAT3 axis also plays an important role in lymphomas ( 82 ) and is crucial for myeloid cell colonization at future metastatic sites in prostate and melanoma cancers ( 83 ). We have recently extended these observations and shown that S1P produced by upregulation of SphK1 during colitis and associated cancer is essential for production of the multifunctional NF-kB-regulated cytokine IL-6, persistent activation of the transcription factor STAT3, and consequent upregulation of the S1PR, S1PR1.…”

An update on the biology of sphingosine 1-phosphate receptors

“…AKT and Bcl-associated death promoter pro-survival pathways were also reduced by FTY720 administration to neuroblastoma cells in an in vitro and an in vivo xenograft model, resulting in decreased cancer cell viability ( 175 ). S1PR expression in several hematological malignancies has also been described, including S1P 1 expression by classical Hodgkin's lymphoma (CHL) cells, B cell chronic lymphocytic leukemia (B-CLL) cells, and activated B celllike DLBCL cells (176)(177)(178). Chronic myeloid leukemia (CML) cells expressed S1P 2 , which resulted in increased stability of the B cell receptor-Abl1 fusion protein and subsequently, increased proliferation ( 179 …”