title: KL1 internal repeat mediates klotho tumor suppressor activities and inhibits bFGF and IGF-I signaling in pancreatic cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Institute of Oncology, The Chaim Sheba Medical Center, Ramat-Gan, Tel Aviv, Israel.
authors.forename: Lilach
authors.initials: L
authors.lastname: Abramovitz
authors.forename: Tamar
authors.initials: T
authors.lastname: Rubinek
authors.forename: Hagai
authors.initials: H
authors.lastname: Ligumsky
authors.forename: Shikha
authors.initials: S
authors.lastname: Bose
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.forename: Camila
authors.initials: C
authors.lastname: Avivi
authors.forename: Bella
authors.initials: B
authors.lastname: Kaufman
authors.forename: Ido
authors.initials: I
authors.lastname: Wolf
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000089703:Fibroblast Growth Factor-23; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000235:genetics; D000090265:Klotho Proteins; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D025521:Tumor Suppressor Proteins; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins