title: Reduced expression and growth inhibitory activity of the aging suppressor klotho in epithelial ovarian cancer.
abstract: Klotho is an anti-aging transmembrane protein, which can be shed and function as a hormone. Accumulating data indicate klotho as a tumor suppressor in a wide array of malignancies, and we identified klotho as an inhibitor of the insulin-like growth factor (IGF-1) pathway in cancer cells. As this pathway is significant in the development of epithelial ovarian cancer (EOC) we studied klotho expression and activity in this tumor. Klotho mRNA levels were reduced in 16 of 19 EOC cell lines and immunohistochemistry analysis revealed high expression in normal ovaries, and reduced expression in 100 of 241 high grade papillary-serous adenocarcinoma of the ovaries, fallopian tubes and peritoneum. Reduced expression was associated with wild-type BRCA status. Klotho reduced EOC cell viability, enhanced cisplatin sensitivity, and reduced expression of mesenchymal markers. Finally, klotho inhibited IGF-1 pathway activation and inhibited transcriptional activity of the estrogen receptor. In conclusion, klotho is silenced in a substantial subset of the tumors and restoring its expression slows growth of EOC cells and inhibits major signaling pathways. As klotho is a hormone, treatment with klotho may serve as a novel treatment for EOC.
authors.affiliation: Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Irina
authors.initials: I
authors.lastname: Lojkin
authors.affiliation: Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Tami
authors.initials: T
authors.lastname: Rubinek
authors.affiliation: Women's Cancer Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Orsulic
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Omer
authors.initials: O
authors.lastname: Schwarzmann
authors.affiliation: Women's Cancer Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.affiliation: Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Shikha
authors.initials: S
authors.lastname: Bose
authors.affiliation: Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: wolf-i@inter.net.il.
authors.forename: Ido
authors.initials: I
authors.lastname: Wolf
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005966:Glucuronidase / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism; D000090265:Klotho Proteins; D061986:MCF-7 Cells; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Estrogen receptor; Klotho; Ovarian cancer; Tumor suppressor