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

描述（由申请人提供）：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破坏。骨髓基质细胞（BMSCs）被认为是微环境支持MM细胞生长和骨破坏的关键角色。x- box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，我们发现与正常供体骨髓间充质干细胞相比，MM患者骨髓间充质干细胞中XBP1s被强烈诱导。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，我们提出MM细胞在骨髓间充质干细胞中诱导XBP1s信号传导。在MM骨病中，XBP1s信号在调节BMSCs支持MM细胞生长和破骨细胞（OCL）分化中发挥重要作用。此外，白藜芦醇抑制骨髓间充质干细胞中的XBP1s信号，显著降低骨髓间充质干细胞支持MM细胞生长和破骨细胞发生的能力。检验这些假设,我们将1)确定调制XBP1s信号在人类bmsc影响hBMSCs的MM细胞生长和破骨细胞分化的支持通过功能和功能丧失战略,2)阐明XBP1s蛋白质水平的分子机制诱导bmsc的MM骨病,和3)确定白藜芦醇压制XBP1s信号在毫米bmsc和妥协他们的支持增长和osteoclastogenesis体外和体内。这些研究将为骨髓间充质干细胞对MM细胞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其抗肿瘤作用的新分子靶点。

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. PUBLIC HEALTH RELEVANCE: The primary goals of this research proposal are to determine 1) if XBP1s signaling plays a critical role in regulating the capacity of bone marrow stromal cells to support MM cell growth and osteoclastogenesis, and 2) if Resveratrol, an activator of SIRT1 and a bioactive dietary component of red wine, represses XBP1s signaling in BMSCs and compromises their support of MM growth and osteoclastogenesis. These studies will provide important information to develop nutritional and pharmacological strategies involving Resveratrol to reduce MM in humans.