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 overexpression 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. Mol Cancer Ther; 16(11); 2516–27. ©2017 AACR .

中文翻译：

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Sphingosine-1-Phosphate Receptor-1促进环境调节和获得的化学抗性

耐药性是发展有效和持久的癌症疗法的主要障碍。克服这一挑战需要进一步定义潜在耐药性的细胞和分子机制，包括获得性耐药和环境介导的耐药性（EMDR）。在这里，我们使用神经母细胞瘤（NB）作为一种儿童期癌症，由于其对化学疗法的抗药性高复发率，作为模型，我们显示了人骨髓间充质基质细胞诱导鞘氨醇-1-磷酸受体1（S1PR1）的肿瘤表达，导致其对化学疗法的抵抗力。通过shRNA靶向S1PR1可以显着增强依托泊苷诱导的NB细胞凋亡并消除EMDR，而S1PR1的过表达则可以通过激活JAK–STAT3信号传导显着保护NB细胞免于多种药物诱导的凋亡。在具有对依托泊苷的获得性抗性的人NB细胞中也观察到S1PR1表达升高和STAT3激活。我们在体外和人NB异种移植模型中显示，用FTY720（一种FDA批准的药物和S1PR1拮抗剂）进行治疗，可使耐药细胞对依托泊苷显着敏感。总之，我们确定S1PR1是降低NB中EMDR和获得性化学耐药性的关键目标。分子癌疗法；16（11）; 2516–27。©2017 AACR。2516–27。©2017 AACR。2516–27。©2017 AACR。