Abstract
BackgroundThe 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.MethodsMethylation 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.ResultsMethylation 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.ConclusionKlotho 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.
Highlights
Gastric cancer (GC) is the fourth most prevalent cancer and the second leading cause of cancer-related deaths worldwide [1]
A number of studies revealed that insulin/insulin-like growth factor-1 (IGF-1) and Phosphoinositide 3-kinase (PI3K)/Protein Kinase B (Akt)/Mammalian target of rapamycin (mTOR) signaling pathways are involved in the carcinogenesis of gastric cancer (GC) through inhibiting cell apoptosis [4,7]
We investigated the involvement of klotho in GC cell apoptosis and autophagy as well as the associated signaling by delivering klotho gene expression vector into two GC cell lines
Summary
Gastric cancer (GC) is the fourth most prevalent cancer and the second leading cause of cancer-related deaths worldwide [1]. TP53 is one of the earliest reported frequently mutated tumor suppressor genes in primary GC, a growing number of genetic and epigenetic alterations in other tumor suppressors have been reported to be involved in the carcinogenesis of GC [2]. Tyrosine phosphorylation of the insulin/IGF-1 receptors induces cytoplasmic binding of insulin receptor substrate 1 (IRS-1) to these receptors and phosphorylation of multiple tyrosine residues of IRS-1 itself This enables IRS-1 to activate several signaling pathways, including the PI3K (phos-phoinositide 3-kinase) / Akt / mTOR signaling and MAP kinase pathways. A number of studies revealed that insulin/IGF-1 and PI3K/Akt/mTOR signaling pathways are involved in the carcinogenesis of GC through inhibiting cell apoptosis [4,7]. Klotho is a recently identified tumor suppressor gene that epigenetically inactivated in gastric cancer. We investigated the involvement of klotho in gastric cancer cell proliferation, apoptosis, and autophagy as well as the associated signaling
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