Osteoblast‐derived sphingosine 1‐phosphate to induce proliferation and confer resistance to therapeutics to bone metastasis‐derived prostate cancer cells

Abstract

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.

Sphingolipid metabolism in cancer signalling and therapy

“…In addition, understanding the roles of sphingolipid signalling in the regulation of communication between tumours and host cells associated with the tumour microenvironment 105–110 , including stromal cells, endothelial cells, osteoclasts or platelets, will help to develop novel therapeutic strategies to inhibit cancer growth, proliferation and/or metastasis. Moreover, additional studies are needed to determine how sphingolipid signalling can be altered to increase the antitumour functions of T cells and decrease the suppressor functions of myeloid-derived suppressor cells and/or tumour-associated macrophages to improve the anticancer efficacy of immunotherapy.…”

“…4). Moreover, osteoblast-derived systemic S1P also induced proliferation and docetaxel resistance in bone-metastasis-derived prostate cancer cells 110 . Thus, these data suggest a key role for systemic S1P signalling in regulation of tumour growth and/or metastasis, in part by inducing S1PR signalling in tumour cells.…”

Sphingosine 1-phosphate signaling in bone remodeling: multifaceted roles and therapeutic potential

“…Furthermore, during the early phase response [33], bone injury is accompanied by a local platelet activation and platelet-mediated secretion of a platelet-derived growth factor (PDGF) and likely S1P. Osteoclasts and osteoblastic cells also secrete substantial amounts of S1P within the bone microenvironment [34,35].

Figure 2.Interconnected processes of (i) S1P synthesis and degradation within the sphingomyelin/salvage pathway, (ii) S1P export and (iii) signaling through binding to five specific G-protein-coupled receptors, S1PR1-5.

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Examining impacts of ceranib-2 on the proliferation, morphology and ultrastructure of human breast cancer cells

“…For instance, several enzymes such as ceramidases that reduce ceramide levels, lead to anti-apoptotic, prosurvival and/or resistance to chemotherapy in various cancer cells (Kolesnick 2002). Acid ceramidase is an enzyme that metabolize ceramides to sphingosine-1-phosphate which has antiproliferative activity and promotes apoptotic cell death (Beckham et al 2013;Brizuela et al 2014). This enzyme is overexpressed in prostate and breast cancers (Sanger et al 2015).…”