Institute of Oncology, The Chaim Sheba Medical Center, Ramat-Gan, Tel Aviv, Israel.
Clin Cancer Res. 2011 Jul 1;17(13):4254-66. doi: 10.1158/1078-0432.CCR-10-2749. Epub 2011 May 13.
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.
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.
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.
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.
Klotho 是一种跨膜蛋白，可被切割，作为一种循环激素发挥作用，并调节胰岛素样生长因子 (IGF)-I 和成纤维细胞生长因子 (FGF) 途径。我们最近发现 Klotho 是乳腺癌的一种肿瘤抑制因子。Klotho 在正常胰腺中表达，而 IGF-I 和 FGF 途径都参与胰腺癌的发展。因此，我们着手研究 Klotho 在胰腺癌中的表达和活性。
使用免疫组织化学和定量 RT-PCR 研究 Klotho 的表达。使用集落和 MTT 测定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。通过 Western blot 测定信号通路活性。
Klotho 在胰腺腺癌中表达下调。Klotho 的过表达或可溶性 Klotho 的治疗在体外和体内均降低了胰腺癌细胞的生长，并抑制了 IGF-I 和 bFGF 途径的激活。KL1 是由切割或选择性剪接形成的 Klotho 亚结构域。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，其给予小鼠显示出良好的安全性特征。
这些研究表明 Klotho 是胰腺癌的一种潜在肿瘤抑制因子，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 Klotho 或 KL1 可作为开发用于治疗胰腺癌的新型治疗干预措施的潜在策略。
