A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition

Abstract

Tumor metastasis is not only a sign of disease severity but also a major factor causing treatment failure and cancer-related death. Therefore, studies on the molecular mechanisms of tumor metastasis are critical for the development of treatments and for the improvement of survival. The epithelial-mesenchymal transition (EMT) is an orderly, polygenic biological process that plays an important role in tumor cell invasion, metastasis and chemoresistance. The complex, multi-step process of EMT involves multiple regulatory mechanisms. Specifically, the PI3K/Akt signaling pathway can affect the EMT in a variety of ways to influence tumor aggressiveness. A better understanding of the regulatory mechanisms related to the EMT can provide a theoretical basis for the early prediction of tumor progression as well as targeted therapy.

Keywords: CK, cytokeratin; ECM, extracellular matrix; EMT; EMT, epithelial-mesenchymal transition; FGF, fibroblast growth factor; GSK-3β, glycogen synthase kinase 3 β; ILK, integrin-linked kinase; MDR, multidrug resistance; MET, mesenchymal-epithelial transition; PDGF, platelet-derived growth factor; PDK1, 3-phosphoinositide-dependent protein kinase 1; PI3K, phosphatidylinositol-3-kinase; PI3K/Akt signaling pathway; PKA, protein kinase A; PKB, protein kinase B; PKC, protein kinase C; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; YB-1, Y-box binding protein-1; anti-cancer therapy; bHLH, basic helix-loop-helix protein; extracellular matrix; transcription factors; tumor aggressiveness.

Figure 1.

The characteristics, regulators and effects of the epithelial-mesenchymal transition (EMT). The EMT is an orderly process whereby epithelial cells lose their phenotype and gradually acquire the phenotype of mesenchymal cells. This process is accompanied by changes in the physical contacts between cells as well as in cellular polarity, cellular morphology, and biomarkers. The PI3K/Akt signaling pathway cooperates with other signaling pathways, either directly or indirectly, to induce the EMT. This results in enhanced tumor aggressiveness, including proliferation, apoptosis resistance, invasion, metastasis and chemoresistance.