Sphingosine-1-Phosphate Receptor-1 Promotes Environment-Mediated and Acquired Chemoresistance

Abstract

Drug resistance is a major barrier for the development of effective and durable cancer therapies. Overcoming this challenge requires further defining the cellular and molecular mechanisms underlying drug resistance, both acquired and environment-mediated drug resistance (EMDR). Here, using neuroblastoma (NB), a childhood cancer with high incidence of recurrence due to resistance to chemotherapy, as a model we show that human bone marrow-mesenchymal stromal cells induce tumor expression of sphingosine-1-phosphate receptor-1 (S1PR1) leading to their resistance to chemotherapy. Targeting S1PR1 by shRNA markedly enhances etoposide-induced apoptosis in NB cells and abrogates EMDR, while over-expression of S1PR1 significantly protects NB cells from multidrug-induced apoptosis via activating JAK-STAT3 signaling. Elevated S1PR1 expression and STAT3 activation are also observed in human NB cells with acquired resistance to etoposide. We show in vitro and in human NB xenograft models that treatment with FTY720, an FDA-approved drug and antagonist of S1PR1, dramatically sensitizes drug-resistant cells to etoposide. In summary, we identify S1PR1 as a critical target for reducing both EMDR and acquired chemoresistance in NB.

Endoplasmic reticulum resident oxidase ERO1-Lalpha promotes hepatocellular carcinoma metastasis and angiogenesis through the S1PR1/STAT3/VEGF-A pathway

“…S1PR1, one of the five G protein-coupled receptors for S1P, is crucial for the retention of lymphocytes of secondary lymphoid organs 16 , 17 and tumor angiogenesis and metastasis 18 , 19 . A study identified S1PR1 as a critical target for reducing acquired and environment-mediated drug resistance in neuroblastoma 31 . S1P is a potent bioactive sphingolipid metabolite that regulates cell growth, survival, differentiation, lymphocyte trafficking, vascular integrity, and cytokine and chemokine production that are important for inflammation and immune responses 15 , 16 .…”

Does Fingolimod have anticancer effects? A meta-analysis and systematic review based on experimental animal models of various cancers

“…Literature screening and the summary of 31 studies Using "FTY720" or/and "animals" or/and "cancer" as the index, only 31 studies including 44 experiments of a total of 1485 research papers met our research criteria. The ow diagram for meta-analysis in detail was displayed in Fig. (Alshaker et al 2017;Azuma et al 2002;Chen et al 2014;Chua et al 2005;Estrada-Bernal et al 2012;Gstalder et al 2016;Hait et al 2015;Ho et al 2005;Katsuta et al 2017;Kreitzburg et al 2018;Lankadasari et al 2018; Lee et al 2004;Lee et al 2005;Leu et al 2016;Li et al 2013;Li et al 2018;Li et al 2017;Lifshitz et al 2017;Liu et al 2015;Liu et al 2014;Markovsky et al 2019;Martin et al 2017;Mousseau et al 2012;Muroyama et al 2017;Nagahashi et al 2016;Pchejetski et al 2010;Rosa et al 2013;Schmid et al 2007;Szymiczek et al 2017;Woo et al 2015;Xu et al 2015). Table S1 discussed study characteristics of 31 published articles from 1998 to 2019.…”

“…More deeply, we summarized the toxicity reaction of FTY720 alone or in combination from every original study in Table S4. 16 of the total 31 articles related to side effect of FTY720, and showed no obvious side effects in mice and rats during their experiment (Alshaker et al 2017;Chua et al 2005;Gstalder et al 2016;Hait et al 2015;Ho et al 2005;Katsuta et al 2017;Lee et al 2004;Lee et al 2005;Leu et al 2016;Li et al 2017;Lifshitz et al 2017;Martin et al 2017;Pchejetski et al 2010;Rosa et al 2013;Szymiczek et al 2017;Xu et al 2015). The remaining 15 articles didn't document explicitly for the potential side effects of FTY720.…”

“…Signaling pathway related with FTY720 anticancer mechanism Finally, the anticancer related molecular signals of FYP720 alone or in combination with chemical drug in total 26 articles were summarized in Table 1. The main molecular mechanism was focused on apoptosis which was discussed by 20 articles, including non-small lung cancer, pancreatic cancer, mesothelioma, breast cancer, renal cell carcinoma, colorectal cancer, adrenocortical carcinoma, acute myeloid leukemia, neuroblastoma, glioblastoma, prostate cancer, and hepatocellular carcinoma (Alshaker et al 2017;Chen et al 2014;Chua et al 2005;Estrada-Bernal et al 2012;Gstalder et al 2016;Ho et al 2005;Lankadasari et al 2018;Lee et al 2004;Lee et al 2005;Li et al 2013;Li et al 2017;Lifshitz et al 2017;Liu et al 2015;Martin et al 2017;Mousseau et al 2012;Pchejetski et al 2010;Rosa et al 2013;Szymiczek et al 2017;Woo et al 2015;Xu et al 2015). In the remaining signal pathway, six involved metastasis (pancreatic cancer, breast cancer, pancreatic cancer, non-small cell lung cancer, hepatocellular carcinoma and androgen-independent prostate cancer) (Azuma et al 2003;Chua et al 2005 arrest (androgen-independent prostate cancer, acute myeloid leukemia, hepatocellular carcinoma) (Chua et al 2005;Ho et al 2005;Lee et al 2004;Lee et al 2005), four involved angiogenesis (hepatocellular carcinoma, Lewis lung cancer, androgen-independent prostate cancer, breast cancer) (Chua et al 2005;Ho et al 2005;Mousseau et al 2012;Schmid et al 2007), two involved invasion (non-small lung cancer, adrenocortical carcinoma) (Liu...…”

Mesenchymal Stromal Cells in Neuroblastoma: Exploring Crosstalk and Therapeutic Implications

“…Chemoresistance in NB was shown to involve MSC-mediated STAT3 signaling in in vitro experiments: NB cells cocultured with patient-derived BM-MSCs were protected from etoposide-induced apoptosis [ 73 , 179 , 180 ]. The results suggested Sphingosine-1-phosphate receptor 1 (S1PR1) to play a role in the activation of STAT3 signaling in NB cells and showed that antiapoptotic proteins Bcl2 and survivin are involved in the STAT3-related chemoresistance mechanism [ 179 , 180 ]. Consistently, knockdown or inhibition of S1PR1 abrogated the STAT3-mediated chemoresistance [ 179 ].…”