Brizuela Leyre, Martin Claire, Jeannot Pauline, Ader Isabelle, Gstalder Cécile, Andrieu Guillaume, Bocquet Magalie, Laffosse Jean-Michel, Gomez-Brouchet Anne, Malavaud Bernard, Sabbadini Roger A, Cuvillier Olivier
CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France; Université de Toulouse, UPS, IPBS, Toulouse, France; Equipe Labellisée Ligue contre le Cancer, France.
Université de Toulouse, UPS, IPBS, Toulouse, France; CHU Toulouse, Service d'orthopédie et Traumatologie, Toulouse, France.
Mol Oncol. 2014 Oct;8(7):1181-95. doi: 10.1016/j.molonc.2014.04.001. Epub 2014 Apr 13.
Sphingosine 1-phosphate (S1P) plays important roles in cell proliferation, differentiation or survival mainly through its surface G-protein-coupled receptors S1P1-5. Bone represents the major site of metastasis for prostate cancer (CaP) cells, which rely on bone-derived factors to support their proliferation and resistance to therapeutics. In the present work we have found that conditioned medium (CM) from the MC3T3 osteoblastic cell line or primary murine and human osteoblast-like cells, as well as co-culture with MC3T3 stimulate proliferation of CaP lines in S1P-dependent manner. In addition, osteoblastic-derived S1P induces resistance of CaP cells to therapeutics including chemotherapy and radiotherapy. When S1P release from osteoblastic cells is decreased (inhibition of SphK1, knock-down of SphK1 or the S1P transporter, Spns2 by siRNA) or secreted S1P neutralized with anti-S1P antibody, the proliferative and survival effects of osteoblasts on CaP cells are abolished. Because of the paracrine nature of the signaling, we studied the role of the S1P receptors expressed on CaP cells in the communication with S1P secreted by osteoblasts. Strategies aimed at down-regulating S1P1, S1P2 or S1P3 (siRNA, antagonists), established the exclusive role of the S1P/S1P1 signaling between osteoblasts and CaP cells. Bone metastases from CaP are associated with osteoblastic differentiation resulting in abnormal bone formation. We show that the autocrine S1P/S1P3 signaling is central during differentiation to mature osteoblasts by regulating Runx2 level, a key transcription factor involved in osteoblastic maturation. Importantly, differentiated osteoblasts exhibited enhanced secretion of S1P and further stimulated CaP cell proliferation in a S1P-dependent manner. By establishing the dual role of osteoblast-borne S1P on both osteoblastic differentiation and CaP cell proliferation and survival, we uncover the importance of S1P in the bone metastatic microenvironment, which may open a novel area of study for the treatment of CaP bone metastasis by targeting S1P.
鞘氨醇-1-磷酸（S1P）主要通过其表面的G蛋白偶联受体S1P1 - 5在细胞增殖、分化或存活中发挥重要作用。骨骼是前列腺癌细胞（CaP）转移的主要部位，前列腺癌细胞依赖骨源性因子来支持其增殖和对治疗的抵抗。在本研究中，我们发现来自MC3T3成骨细胞系或原代小鼠和人成骨样细胞的条件培养基（CM），以及与MC3T3共培养，以S1P依赖的方式刺激CaP细胞系的增殖。此外，成骨细胞衍生的S1P诱导CaP细胞对包括化疗和放疗在内的治疗产生抗性。当成骨细胞中S1P的释放减少（抑制鞘氨醇激酶1（SphK1）、通过小干扰RNA（siRNA）敲低SphK
