S1PR1 as a Novel Promising Therapeutic Target in Cancer Therapy

摘要

Sphingosine-1-phosphate (S1P) can regulate several physiological and pathological processes. S1P signaling via its cell surface receptor S1PR1 has beenshown to enhance tumorigenesis and stimulate growth, expansion, angiogenesis, metastasis, and survival of cancer cells. S1PR1-mediated tumorigenesis is supported and amplified by activation of downstream effectors including STAT3, interleukin-6, and NF-kappa B networks. S1PR1 signaling can also trigger various othersignaling pathways involved in carcinogenesis including activation of PI3K/AKT, MAPK/ERK1/2, Rac, and PKC/Ca, as well as suppression of cyclic adenosine monophosphate (cAMP). It also induces immunological tolerance in the tumor microenvironment, while the immunosuppressive function of S1PR1 can also lead to thegeneration of pre-metastatic niches. Some tumor cells upregulate S1PR1 signaling pathways, which leads to drug resistant cancer cells, mainly through activation of STAT3. This signaling pathway is also implicated in some inflammatory conditions leading to theinstigation of inflammation-driven cancers. Furthermore, it canalso increase survival via induction of anti-apoptotic pathways, for instance, in breast cancer cells. Therefore, S1PR1 and its signaling pathways can be considered as potential anti-tumor therapeutic targets, alone or in combination therapies. Given the oncogenic natureof S1PR1 and its distribution in a variety of cancer cell typesalong withits targeting advantages over other molecules of this family, S1PR1 should be considereda favorable target in therapeutic approaches tocancer. This review describes the role of S1PR1 in cancer development and progression, specifically addressing breast cancer, glioma, and hematopoietic malignancies. We also discuss the potential use of S1P signaling modulators as therapeutic targets in cancer therapy.