Ron knockdown and Ron monoclonal antibody IMC-RON8 sensitize pancreatic cancer to histone deacetylase inhibitors (HDACi).
Ron knockdown and Ron monoclonal antibody IMC-RON8 sensitize pancreatic cancer to histone deacetylase inhibitors (HDACi).
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DOI：
10.1371/journal.pone.0069992
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Brattain MG
中科院分区：
文献类型：
--
作者：
Zou Y;Howell GM;Humphrey LE;Wang J;Brattain MG
南泰受体 (Ron) 在一组胰腺癌细胞和胰腺癌患者的组织样本中过度表达。 Ron可被其配体巨噬细胞刺激蛋白（MSP）激活，从而激活致癌信号通路。 Ron 和 EGFR、c-Met 或 IGF-1R 之间的串扰可能提供了耐药性的潜在机制。因此，针对 Ron 可能代表一种新颖的治疗策略。 IMC-RON8是第一个进入临床试验的针对Ron过度表达的Ron单克隆抗体(mAb)。我们的研究表明，IMC-RON8 下调了胰腺癌细胞中的 Ron 表达，并显着阻断了 MSP 刺激的 Ron 激活、下游 Akt 和 ERK 磷酸化以及生存素 mRNA 表达。 IMC-RON8 阻碍 MSP 诱导的细胞迁移并减少细胞转化。据报道，组蛋白脱乙酰酶抑制剂 (HDACi) 通过修饰核小体组蛋白和非组蛋白来靶向多种基因的表达。我们的工作表明 HDACi TSA 和 Panobinostat (PS) 降低了胰腺癌细胞中 Ron mRNA 和蛋白质的表达。 PS 还减少 pAkt、生存素和 XIAP 的下游信号传导，并增强细胞凋亡。有趣的是，在集落形成和软琼脂糖测定中，PS 比 Ron 扰乱对照细胞更大程度地减少了 Ron 敲低细胞中的集落形成。 IMC-RON8 还可以使胰腺癌细胞对 PS 敏感，与单独治疗相比，IMC-RON8 和 PS 联合治疗的集落数量和大小减少就反映了这一点。与单独治疗相比，联合治疗进一步降低了 Ron 表达和 pAkt，并增加了 PARP 裂解。这项研究表明了一种新的组合方法的潜力，该方法最终可能对胰腺癌的治疗有价值。
Recepteur d’origine nantais (Ron) is overexpressed in a panel of pancreatic cancer cells and tissue samples from pancreatic cancer patients. Ron can be activated by its ligand macrophage stimulating protein (MSP), thereby activating oncogenic signaling pathways. Crosstalk between Ron and EGFR, c-Met, or IGF-1R may provide a mechanism underlying drug resistance. Thus, targeting Ron may represent a novel therapeutic strategy. IMC-RON8 is the first Ron monoclonal antibody (mAb) entering clinical trial for targeting Ron overexpression. Our studies show IMC-RON8 downmodulated Ron expression in pancreatic cancer cells and significantly blocked MSP-stimulated Ron activation, downstream Akt and ERK phosphorylation, and survivin mRNA expression. IMC-RON8 hindered MSP-induced cell migration and reduced cell transformation. Histone deacetylase inhibitors (HDACi) are reported to target expression of various genes through modification of nucleosome histones and non-histone proteins. Our work shows HDACi TSA and Panobinostat (PS) decreased Ron mRNA and protein expression in pancreatic cancer cells. PS also reduced downstream signaling of pAkt, survivin, and XIAP, as well as enhanced cell apoptosis. Interestingly, PS reduced colony formation in Ron knockdown cells to a greater extent than Ron scramble control cells in colony formation and soft agarose assays. IMC-RON8 could also sensitize pancreatic cancer cells to PS, as reflected by reduced colony numbers and size in combination treatment with IMC-RON8 and PS compared to single treatment alone. The co-treatment further reduced Ron expression and pAkt, and increased PARP cleavage compared to either treatment alone. This study suggests the potential for a novel combination approach which may ultimately be of value in treatment of pancreatic cancer.
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