Gastrokine 1 induces senescence and apoptosis through regulating telomere length in gastric cancer

Abstract

The present study aims to investigate whether gastrokine 1 (GKN1) induces senescence and apoptosis in gastric cancer cells by regulating telomere length and telomerase activity. Telomere length, telomerase activity, and hTERT expression decreased significantly in AGS^GKN1 and MKN1^GKN1 cells. Both stable cell lines showed increased expression of TRF1 and reduced expression of the hTERT and c-myc proteins. In addition, TRF1 induced a considerable decrease in cell growth, telomerase activity, and expression of hTERT mRNA and protein. GKN1 completely counteracted the effects of c-myc on cell growth, telomere length, and telomerase activity. Interestingly, GKN1 directly bound to c-myc and down-regulated its expression as well as inhibited its binding to the TRF1 protein and a hTERT promoter. Furthermore, GKN1 triggered senescence, followed by apoptosis via up-regulating the p53, p21, p27, and p16 proteins and down-regulating Skp2. Telomere length in 35 gastric cancers was shortened significantly compared with the corresponding gastric mucosae, whereas GKN1 expression was inversely correlated with telomere length and c-myc and hTERT mRNA expression. Taken together, these results suggest that GKN1 may shorten telomeres by acting as a potential c-myc inhibitor that eventually leads to senescence and apoptosis in gastric cancer cells.