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针对多发性骨髓瘤（MM）化疗耐药的新疗法。拟议项目的目标是阐明MM细胞中维持化疗耐药性的方式，这对于实现我们的长期研究目标至关重要，因为它将提供对治疗靶向机制的更好理解，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（AD）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MM患者的BM比非复发性疾病患者的BM含有显著更多的AD，并且MM细胞包围并接触AD。我们发现与AD共培养可保护MM细胞免受化疗诱导的凋亡，并且AD分泌的脂肪因子chemerin是介导AD保护MM细胞免受化疗的新因子。此外，与MM细胞共培养增强了AD形成和AD的chemerin产生，并且添加针对Wnt抑制剂dickkopf-1（DKK-1）的抗体消除了这种作用。微阵列数据的分析显示，在与AD共培养的MM细胞中上调的蛋白质包括自噬蛋白如Beclin-1和信号激酶如AMPK，其参与MM细胞增殖和细胞死亡。阵列数据还显示，在与MM细胞共培养的AD中上调的蛋白质包括AD相关蛋白和转录因子，如PPAR γ 2，其参与AD分化和AD产生脂肪因子。基于这些新的发现，我们推测MM分泌的DKK-1增强AD分化和chemerin分泌，而AD分泌的chemerin反过来保护MM细胞免受化疗诱导的凋亡。在这项研究中，我们将确定AD分泌的chemerin是否通过激活AMPK和抑制mTOR诱导自噬，从而抑制MM细胞凋亡。我们还将确定MM分泌的DKK-1是否激活PPAR γ，从而通过抑制Wnt/β-连环蛋白信号传导来增强AD分化和AD的chemerin产生。成功完成拟议工作所获得的知识将通过制定新的策略来对抗复发性或难治性疾病，从而改善MM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.