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Reduced expression and growth inhibitory activity of the aging suppressor klotho in epithelial ovarian cancer
Irina Lojkin1, Tami Rubinek2, Sandra Orsulic3
1Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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.
Insights
Klotho protein, an anti-aging hormone, acts as a tumor suppressor. Restoring klotho in epithelial ovarian cancer (EOC) slows tumor growth and inhibits key cancer pathways, suggesting a novel therapeutic approach.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Klotho is an anti-aging protein functioning as a hormone.
- Klotho acts as a tumor suppressor by inhibiting the insulin-like growth factor-1 (IGF-1) pathway.
- The IGF-1 pathway is implicated in epithelial ovarian cancer (EOC) development.
Purpose of the Study:
- To investigate klotho expression and its functional role in epithelial ovarian cancer (EOC).
- To determine if klotho can inhibit EOC cell growth and signaling pathways.
Main Methods:
- Analysis of klotho mRNA levels in EOC cell lines.
- Immunohistochemistry to assess klotho protein expression in human EOC tissues.
- In vitro studies to evaluate klotho's effects on EOC cell viability, cisplatin sensitivity, and signaling pathways (IGF-1, estrogen receptor).
Main Results:
- Klotho mRNA was reduced in most EOC cell lines.
- Reduced klotho protein expression was observed in a significant proportion of EOC tumors, particularly those with wild-type BRCA status.
- Klotho suppressed EOC cell viability, increased sensitivity to cisplatin, and inhibited IGF-1 and estrogen receptor signaling.
Conclusions:
- Klotho is frequently silenced in EOC.
- Restoring klotho expression inhibits EOC cell growth and key oncogenic signaling pathways.
- Therapeutic administration of klotho may represent a novel treatment strategy for EOC.
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