Inhibition of endoglin-GIPC interaction inhibits pancreatic cancer cell growth.
Inhibition of endoglin-GIPC interaction inhibits pancreatic cancer cell growth.
复制标题
DOI：
10.1158/1535-7163.mct-14-0291
复制
发表时间：
2014-10
影响因子：
5.7
通讯作者：
Mukhopadhyay D
中科院分区：
文献类型：
--
作者：
Pal K;Pletnev AA;Dutta SK;Wang E;Zhao R;Baral A;Yadav VK;Aggarwal S;Krishnaswamy S;Alkharfy KM;Chowdhury S;Spaller MR;Mukhopadhyay D
Endoglin是一种180 kDa二硫键连接的同源二聚体跨膜受体蛋白，主要在肿瘤相关内皮细胞中表达，是GAIP相互作用蛋白C末端（GIPC）的内源性结合伴侣。内皮糖蛋白作为结合转化生长因子-β（TGF-β）的TβRII的共受体起作用，并且对于血管发育是重要的，因此已经成为抗血管生成疗法的引人注目的靶标。然而，最近在胃肠道间质瘤（GIST）、乳腺癌和卵巢癌中的一些研究表明，内皮糖蛋白在肿瘤细胞中上调，并且与不良预后相关。这些发现表明内皮糖蛋白在肿瘤生物学中的更广泛作用，超出了抗血管生成作用。我们当前研究的目标是评估靶向内皮糖蛋白在体外和体内胰腺癌中的作用。我们分析了胰腺癌细胞系中内皮糖蛋白的基于RNAi和基于肽配体的抑制的抗增殖作用，后者产生具有显著抗增殖活性的GIPC PDZ结构域靶向脂肽。我们进一步证明了内皮糖蛋白抑制诱导胰腺癌细胞的分化表型，并使其对常规化疗药物吉西他滨敏感。最重要的是，我们已经证明了基于RNAi和基于竞争性抑制剂的内皮糖蛋白阻断在胰腺癌异种移植模型中的体内抗肿瘤作用。据我们所知，这是第一个报告探讨靶向内皮糖蛋白在胰腺癌细胞中的作用。
Endoglin, a 180 kDa disulfide-linked homodimeric, transmembrane receptor protein mostly expressed in tumor-associated endothelial cells, is an endogenous binding partner of GAIP-interacting protein, C terminus (GIPC). Endoglin functions as a co-receptor of TβRII that binds Transforming Growth Factor-β (TGF-β) and is important for vascular development, and consequently has become a compelling target for anti-angiogenic therapies. A few recent studies in Gastrointestinal Stromal Tumor (GIST), breast cancer and ovarian cancer, however, suggest that endoglin is upregulated in tumor cells and is associated with poor prognosis. These findings indicate a broader role of endoglin in tumor biology, beyond anti-angiogenic effects. The goal of our current study is to evaluate the effects of targeting endoglin in pancreatic cancer both in vitro and in vivo. We analyzed the anti-proliferative effect of both RNAi-based and peptide ligand-based inhibition of endoglin in pancreatic cancer cell lines, the latter yielding a GIPC PDZ domain-targeting lipopeptide with notable anti-proliferative activity. We further demonstrated that endoglin inhibition induced a differentiation phenotype in the pancreatic cancer cells and sensitized them against conventional chemotherapeutic drug gemcitabine. Most importantly, we have demonstrated the anti-tumor effect of both RNAi based and competitive inhibitor based blocking of endoglin in pancreatic cancer xenograft models in vivo. To our knowledge, this is the first report exploring the effect of targeting endoglin in pancreatic cancer cells.