Restoration of klotho gene expression induces apoptosis and autophagy in gastric cancer cells: tumor suppressive role of klotho in gastric cancer

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• 作者：Biao Xie (1) (2)
  Jianping Zhou (1)
  Guoshun Shu (1)
  Dong-cai Liu (1)
  Jiapeng Zhou (1)
  Jinhui Chen (2)
  Lianwen Yuan (1)
  
• 关键词：Klotho ; Gastric cancer ; Apoptosis ; Autophagy
• 刊名：Cancer Cell International
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：13
• 期：1
• 全文大小：672KB
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• 作者单位：Biao Xie (1) (2)
  Jianping Zhou (1)
  Guoshun Shu (1)
  Dong-cai Liu (1)
  Jiapeng Zhou (1)
  Jinhui Chen (2)
  Lianwen Yuan (1)
  
  1. Departemt of Geriatric Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
  2. Department of General Surgery, 8th Changsha Hospital, Changsha, Hunan, 410015, China
  

文摘

Background The loss of tumor suppressor gene expression is involved in the carcinogenesis of gastric cancer (GC). Klotho is a recently identified tumor suppressor gene that epigenetically inactivated in gastric cancer. However, the signaling pathways involved in the suppressive role of klotho have rarely been reported in gastric cancer. In this study, we investigated the involvement of klotho in gastric cancer cell proliferation, apoptosis, and autophagy as well as the associated signaling. Methods Methylation of klotho gene promoter in GC-7901, MNK-45 and AGS gastric cancer cells as well as GES-1 normal gastric epithelial cells was detected by bisulfate-based PCR. Restoration of klotho gene expression was established by applying a demethylating agent and delivering aklotho gene expression vector into GC-7901 cells. Cell viability was measured by CCK-8 assay. Cell apoptosis and cycling were analyzed by flow cytometry. Autophagy was measured by detecting LC3-I and LC3-II expression. Protein levels and phosphorylation were measured by Western blot assay. Results Methylation of klotho gene promoter and expression of the klotho gene were detected in GC cells. Restoration of klotho gene expression significantly inhibited cell proliferation, induced cell apoptosis, and increased LC3-I/LC3-II expression in GC cells. Restoration of klotho gene expression downregulated the phosphorylation levels of IGF-1 receptor, IRS-1, PI3K, Akt, and mTOR proteins. Both apoptosis and autophagy inhibitors blocked klotho-induced apoptosis and autophagy. Conclusion Klotho is a tumor suppressor in gastric cancer, which regulates IGF-1R phosphorylation and the subsequent activation of IRS-1/PI3K/Akt/mTOR signaling, tumor cell proliferation, apoptosis, and autophagy.