Targeting adipocyte-secreted chemerin for chemotherapy resistance in myeloma

 描述(由申请人提供)：我们的长期研究目标是开发对抗多发性骨髓瘤(MM)化疗耐药的新疗法。这项拟议项目的目标是阐明MM细胞中化疗耐药的维持方式，这对实现我们的长期研究目标至关重要，因为它将提供对可能以治疗为靶点的机制的更好理解，以减少或预防这种疾病的化疗耐药性。我们的初步研究表明，脂肪细胞(ADS)是MM患者骨髓(BM)基质细胞(BMSCs)的主要类型。这些研究首次表明，复发性多发性骨髓瘤患者的骨髓比未复发患者的骨髓含有明显更多的ADS，而且MM细胞包围和接触ADS。我们发现，与ADS共培养可以保护MM细胞免受化疗诱导的细胞凋亡，AD分泌的脂肪因子趋化蛋白是介导ADS保护MM细胞免受化疗影响的一个新因素。此外，与MM细胞共培养可促进AD的形成和ADS趋化蛋白的产生，而Wnt抑制因子Dickkopf-1(DKK-1)抗体的加入可消除这种作用。基因芯片数据分析显示，在与ADS共培养的MM细胞中上调的蛋白质包括自噬蛋白如Beclin-1和信号通路如AMPK，它们与MM细胞的增殖和细胞死亡有关。阵列数据还显示，与MM细胞共培养的ADS上调的蛋白质包括AD相关蛋白和转录因子，如PPAR2，它们参与了AD的分化和ADS脂肪因子的产生。在这些新发现的基础上，我们假设MM分泌的DKK-1促进AD分化和趋化蛋白的分泌，而AD分泌的趋化蛋白反过来保护MM细胞免受化疗诱导的凋亡。在这项拟议的研究中，我们将确定AD分泌的趋化蛋白是否通过激活AMPK和抑制mTOR来诱导自噬，从而抑制MM细胞的凋亡。我们还将确定MM分泌的DKK-1是否通过抑制Wnt/？-catenin信号而激活PPAR，从而促进AD分化和ADS趋化蛋白的产生。随着拟议工作的成功完成而获得的知识将通过为抗击复发或难治性疾病的新战略的发展而改善对多发性骨髓瘤患者的护理。

 DESCRIPTION (provided by applicant): Our long-term research goal is to develop novel therapies against chemotherapy resistance in multiple myeloma (MM). The goal of the proposed project, which is to elucidate the way in which chemotherapy resistance is maintained in MM cells, is essential to attaining our long-term research goal because it will provide an improved understanding of the mechanisms that could be therapeutically targeted to reduce or prevent chemotherapy resistance in this disease. Our preliminary studies revealed that adipocytes (ADs) are a dominant type of bone marrow (BM) stromal cells (BMSCs) in the BM of MM patients. These studies showed for the first time that the BM of patients with relapsed MM contained remarkably more ADs than the BM of patients with non-relapsed disease did and that MM cells surround and contact ADs. We found that co-culture with ADs protected MM cells against chemotherapy-induced apoptosis and that the AD-secreted adipokine chemerin is a novel factor that mediates ADs' protection of MM cells against chemotherapy. In addition, co-culture with MM cells enhanced AD formation and ADs' production of chemerin, and the addition of an antibody against the Wnt inhibitor dickkopf-1 (DKK-1) abrogated such effects. An analysis of microarray data revealed that the proteins upregulated in MM cells co-cultured with ADs included autophagy proteins such as Beclin-1 and signaling kinases such as AMPK, which are involved in MM cell proliferation and cell death. The array data also revealed that the proteins upregulated in ADs co-cultured with MM cells included AD-related proteins and transcriptional factors such as PPAR2, which are involved in AD differentiation and ADs' production of adipokines. On the basis of these novel findings, we hypothesize that MM-secreted DKK-1 enhances AD differentiation and chemerin secretion and that AD-secreted chemerin in turn protects MM cells against chemotherapy-induced apoptosis. In the proposed study, we will determine whether AD-secreted chemerin induces autophagy, thereby inhibiting MM cell apoptosis, by activating AMPK and inhibiting mTOR. We will also determine whether MM-secreted DKK-1 activates PPAR, thereby enhancing AD differentiation and ADs' production of chemerin, by inhibiting Wnt/ß-catenin signaling. The knowledge gained with the successful completion of the proposed work will improve the care of MM patients by informing the development of new strategies to combat relapsed or refractory disease.