Activation of PI3K/Akt/mTOR signaling pathway triggered by PTEN downregulation in the pathogenesis of Crohn's disease

Abstract

Objective: We aimed to investigate the role of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway and its negative feedback factor, phosphatase and tensin homolog (PTEN), in the pathogenesis of Crohn's disease (CD).

Methods: Peripheral blood was collected from patients with CD and healthy controls while colon tissue samples were collected from CD patients and those complaining of constipation but with normal endoscopic results. CD4⁺ T-cells were isolated from peripheral blood. The expression of PI3K/Akt/mTOR pathway components and PTEN was evaluated in the peripheral CD4⁺ T-cells using polymerase chain reaction and Western blot, and in intestinal mucosal lymphocytes using immunohistochemistry.

Results: mRNA expressions of PI3K, Akt, mTOR, 4E-binding protein 1 (4E-BP1) and phosphate-ribosomal protein S6 kinase (p70S6K) in peripheral CD4⁺ T-cells were upregulated in CD patients compared with healthy controls . However, the differences were not significant (P > 0.05). Western blot showed that the ratios of phospho-Akt: Akt, phosphorylated-4E-BP1: 4E-BP1 and phospho-p70S6K: p70S6K in peripheral CD4⁺ T-cells were higher in CD patients (P < 0.05). The composite staining score of phospho-Akt and phospho-mTOR in intestinal mucosal lymphocytes also increased in patients with CD compared with those with constipation. Both PTEN mRNA and protein expressions in either peripheral CD4⁺ T-cells or mucosal lymphocytes were lower in patients with CD than in the healthy controls and those with constipation.

Conclusions: The PI3K/Akt/mTOR signaling pathway was activated in CD. The activation of the PI3K/Akt/mTOR pathway caused by PTEN downregulation may be involved in the pathogenesis of CD.

Keywords: Crohn's disease; PI3K/Akt/mTOR signaling pathway; etiology; human PTEN protein.