KL1 Internal Repeat Mediates Klotho Tumor Suppressor Activities and Inhibits bFGF and IGF-I Signaling in Pancreatic Cancer
KL1 Internal Repeat Mediates Klotho Tumor Suppressor Activities and Inhibits bFGF and IGF-I Signaling in Pancreatic Cancer
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DOI：
10.1158/1078-0432.ccr-10-2749
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发表时间：
2011-07-01
影响因子：
11.5
通讯作者：
Wolf, Ido
中科院分区：
文献类型：
--
作者：
Abramovitz, Lilach;Rubinek, Tamar;Wolf, Ido
目的：Klotho是一种跨膜蛋白，可作为循环激素，调节胰岛素样生长因子(IGF)- 1和成纤维细胞生长因子（FGF）通路。我们最近发现klotho在乳腺癌中是一种肿瘤抑制因子。Klotho在正常胰腺中表达，IGF-I和FGF通路都参与胰腺癌的发展。因此，我们开始研究klotho在胰腺癌中的表达和活性。实验设计：采用免疫组织化学和定量RT-PCR方法研究Klotho的表达。采用集落法、MTT法和异种移植模型评估klotho对胰腺癌细胞Panc1、MiaPaCa2和Colo357细胞生长的影响。Western blotting检测信号通路活性。结果：Klotho在胰腺腺癌中表达下调。过表达klotho，或用可溶性klotho处理，可在体外和体内降低胰腺癌细胞的生长，并抑制IGF-I和bFGF通路的激活。KL1是由切割或选择性剪接形成的klotho子结构域。与全长蛋白相比，KL1表现出相似的生长抑制活性，但不促进FGF23信号传导。因此，给药小鼠显示出良好的安全性。结论：这些研究表明klotho在胰腺癌中可能是一种潜在的肿瘤抑制因子，并首次表明klotho的肿瘤抑制活性是通过其KL1结构域介导的。这些结果表明，使用klotho或KL1作为开发胰腺癌新治疗干预措施的潜在策略。临床癌症研究；17 (13);4254 - 66。(c) 2011年aacr。
Purpose: Klotho is a transmembrane protein which can be shed, act as a circulating hormone and modulate the insulin-like growth factor (IGF)-I and the fibroblast growth factor (FGF) pathways. We have recently identified klotho as a tumor suppressor in breast cancer. Klotho is expressed in the normal pancreas and both the IGF-I and FGF pathways are involved in pancreatic cancer development. We, therefore, undertook to study the expression and activity of klotho in pancreatic cancer.Experimental Design: Klotho expression was studied using immunohistochemistry and quantitative RT-PCR. Effects of klotho on cell growth were assessed in the pancreatic cancer cells Panc1, MiaPaCa2, and Colo357, using colony and MTT assays and xenograft models. Signaling pathway activity was measured by Western blotting.Results: Klotho expression is downregulated in pancreatic adenocarcinoma. Overexpression of klotho, or treatment with soluble klotho, reduced growth of pancreatic cancer cells in vitro and in vivo, and inhibited activation of the IGF-I and the bFGF pathways. KL1 is a klotho subdomain formed by cleavage or alternative splicing. Compared with the full-length protein, KL1 showed similar growth inhibitory activity but did not promote FGF23 signaling. Thus, its administration to mice showed favorable safety profile.Conclusions: These studies indicate klotho as a potential tumor suppressor in pancreatic cancer, and suggest, for the first time, that klotho tumor suppressive activities are mediated through its KL1 domain. These results suggest the use of klotho or KL1 as potential strategy for the development of novel therapeutic interventions for pancreatic cancer. Clin Cancer Res; 17(13); 4254-66. (C) 2011 AACR.