XBP1s and Resveratrol regulate the BMSCs'support of myeloma growth and osteoclast

描述(申请人提供)：破坏多发性骨髓瘤(MM)微环境的支持作用具有重要的临床意义，因为MM细胞与微环境之间的相互作用促进了肿瘤的生长和骨的破坏。骨髓基质细胞(BMSCs)被认为是支持MM细胞生长和骨破坏的微环境中的关键因素。X盒结合蛋白1(XBP1)信号是最古老的未折叠蛋白反应信号分支。最近，我们发现MM患者的BMSCs与正常供者的BMSCs相比有较强的XBP1s诱导。此外，SIRT1和白藜芦醇(SIRT1的药理激活剂和红酒的生物活性膳食成分)强烈抑制XBP1s的转录活性。因此，我们认为骨髓瘤细胞在骨髓间充质干细胞中诱导XBP1s信号传导。XBP1s信号在调节骨髓间充质干细胞支持多发性骨髓瘤细胞生长和破骨细胞分化中起重要作用。此外，白藜芦醇抑制BMSCs中的XBP1s信号，并显著降低BMSCs支持MM细胞生长和破骨细胞形成的能力。为了验证这些假设，我们将1)确定调控人BMSCs中的XBP1s信号是否通过功能获得和功能丧失策略影响hBMSCs对MM细胞生长和破骨细胞分化的支持；2)阐明在MM骨病中诱导BMSCs中XBP1s蛋白表达的分子机制；以及3)确定白藜芦醇是否抑制BMSCs中的XBP1s信号并在体外和体内影响其对MM生长和破骨细胞形成的支持。这些研究将对骨髓间充质干细胞对MM细胞的保护作用的分子机制提供新的见解，并揭示白藜芦醇可能作用于的新的分子靶点(S)以实现其抗肿瘤作用。

DESCRIPTION (provided by applicant): Disrupting the supportive effects of the multiple myeloma (MM) microenvironment is of major clinical significance since the interactions between MM cells and the microenvironment enhance tumor growth and bone destruction. Bone marrow stromal cells (BMSCs) are considered a key player in the microenvironmental support of MM cell growth and bone destruction. The X-box-binding protein 1 (XBP1) signaling is the most ancient Unfolded Protein Response signaling branch. Recently, we found that XBP1s was strongly induced in BMSCs from MM patients' compared with normal donors' BMSCs. Further, SIRT1 and Resveratrol, a pharmacological activator of SIRT1 and a bioactive dietary component of red wine, strongly inhibited the transcriptional activity of XBP1s. Therefore, we propose that MM cells induce XBP1s signaling in BMSCs. XBP1s signaling plays an important role in regulating BMSCs' support of MM cell growth and osteoclast (OCL) differentiation in MM bone diseases. Further, Resveratrol represses XBP1s signaling in BMSCs and markedly reduces the capacity of BMSCs to support MM cell growth and osteoclastogenesis. To test these hypotheses, we will 1) determine if modulating XBP1s signaling in human BMSCs impacts hBMSCs' support of MM cell growth and osteoclast differentiation via both gain-of-function and loss-of-function strategies, 2) elucidate the molecular mechanisms by which XBP1s protein levels are induced in BMSCs in MM bone disease, and 3) determine if Resveratrol represses XBP1s signaling in BMSCs and compromises their support of MM growth and osteoclastogenesis both in vitro and in vivo. These studies will shed novel insight into the molecular mechanisms underlying the protective effects of BMSCs on MM cells and reveal the novel molecular target(s) that Resveratrol may acts upon to achieve its anti-tumor effects.