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.
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.
|Chen, Qian; Liu, Kai; Robinson, Andria R et al. (2013) DNA damage drives accelerated bone aging via an NF-?B-dependent mechanism. J Bone Miner Res 28:1214-28|