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• W2326861567 abstract "Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FLThe serine/threonine kinase, Akt, plays a key role in regulating the signaling of a multitude of biological processes including cell proliferation, differentiation, migration and survival. In addition, many human cancers commonly display aberrant hyperactivated Akt survival pathway, a phenomenon that is frequent in tumours that have impaired or deletion of the PTEN tumour suppressor gene. Interestingly, we have recently demonstrated that an increase in intracellular O2− could replace the removal of growth factors resulting in the activation of Akt through the inhibition of the tumour suppressor PTEN and inducing an increased expression of the Na+/H+ exchanger 1 (NHE1), mimicking the phenotype of PTEN-null mouse embryonic fibroblasts. The Na+/H+ exchanger 1 (NHE1) is a membrane antiporter that has been described to promote cell survival via a dual mechanisms- defending cell volume and pHi through Na+/H+ exchange and by functioning as a scaffold for the recruitment of a signalplex involving, PI3-Kinase, ERM and Akt. In the present study, we asked whether the hyperactivity of Akt found in cells that have lost the expression of PTEN could influence the expression of NHE-1. We show that the PTEN-null mouse embryonic fibroblast model displayed an increased expression of Na+/H+ exchanger 1 (NHE1) and hyperactivated Akt compared to its PTEN wildtype counterpart. Moreover the half-life of NHE-1 was shown to increase in PTEN-null fibroblasts compared to the wildtype mouse embryonic fibroblasts. Hence, we hypothesized that Akt hyperactivation could influence the stability of NHE-1 expression. Indeed, using drugs such as LY294002 and Wortmannin to inhibit the activation of AKT, we showed that activated Akt had an effect on NHE-1 expression as the decrease in NHE-1 expression correlated with the dephosporylation of Akt, both at the mRNA and protein levels. Similarly, by silencing Akt gene expression, a more prominent decrease in NHE-1 protein expression was observed. Taken together, our data suggest that hyperactivated Akt may play a crucial role in the stability of NHE-1 in PTEN null fibroblasts, a phenomenon not observed in wildtype fibroblasts. Results from these studies could establish that Akt may be involved in the regulation of NHE-1 expression in tumours that have lost the expression of PTEN.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2927. doi:10.1158/1538-7445.AM2011-2927" @default.
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• W2326861567 date "2011-04-15" @default.
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• W2326861567 title "Abstract 2927: Regulation of Na+/H+ exchanger 1 (NHE1) expression by hyperactivation of Akt in PTEN-null mouse embryonic fibroblasts" @default.
• W2326861567 doi "https://doi.org/10.1158/1538-7445.am2011-2927" @default.
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