Inhibition of Akt activity induces the mesenchymal-to-epithelial reverting transition with restoring E-cadherin expression in KB and KOSCC-25B oral squamous cell carcinoma cells

Abstract

Background: The Akt/PKB family of kinases is frequently activated in human cancers, including oral squamous cell carcinoma (OSCC). Akt-induced epithelial-to-mesenchymal transition (EMT) involves downregulation of E-cadherin, which appears to result from upregulation of the transcription repressor Snail. Recently, it was proposed that carcinoma cells, especially in metastatic sites, could acquire the mesenchymal-to-epithelial reverting transition (MErT) in order to adapt the microenvironments and re-expression of E-cadherin be a critical indicator of MErT. However, the precise mechanism and biologic or clinical importance of the MErT in cancers have been little known. This study aimed to investigate whether Akt inhibition would restore the expression of E-cadherin and β-catenin, reduce that of Vimentin, and induce the MErT in OSCC cells with low or negative expression of E-cadherin. We also investigate whether inhibition of Akt activity would affect the E-cadherin repressors and signaling molecules like NF-κB, ERK, and p38.

The pathological significance of Notch1 in oral squamous cell carcinoma

“…In OSCC, Akt signaling has an important role in its progression, 41,42 and inhibition of Akt signaling suppresses malignant phenotype. 43 Recently, growing evidence has indicated a relationship between Notch signaling and tumor cell invasion. 44,45 Our present data demonstrated that the Notch1 expression influences the TNF-a-dependent invasiveness of OSCC cells via the transcriptional regulation of Slug and Twist, important regulators of cell invasion.…”

Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation

“…As described above, downregulation of ZEB1, Slug, Snail, SMA, or Twist is usually induced during MET (49,61,64). It was also found that progesterone (P4) can regulate the expression of Snail and other EMT-relevant proteins in the human breast cancer cell line MB468 and induce cell morphological reversion from mesenchymal to epithelial phenotypes via membrane progesterone receptor a (mPRa; ref.…”

“…43) or by progesterone (P4) in basal phenotype breast cancer (63) was related to the activity of Akt signaling. Intriguingly, inhibition of Akt activity by PIA (Akt inhibitor, phosphatidylinositol ether lipid analogs) decreased NF-kB signaling and led to downregulation of Snail and Twist expression (64). PIA treatment induced the expression of E-cadherin and b-catenin; downregulated vimentin; restored the epithelial morphology of a polygonal shape; and reduced tumor cell migration in KB and KOSCC-25B cells (64).…”

“…Intriguingly, inhibition of Akt activity by PIA (Akt inhibitor, phosphatidylinositol ether lipid analogs) decreased NF-kB signaling and led to downregulation of Snail and Twist expression (64). PIA treatment induced the expression of E-cadherin and b-catenin; downregulated vimentin; restored the epithelial morphology of a polygonal shape; and reduced tumor cell migration in KB and KOSCC-25B cells (64). These findings suggest that Akt is an important intercellular signaling element during the changes in cell phenotype, and its activity is usually repressed during MET.…”

Metastatic breast cancer cells in the bone marrow microenvironment: novel insights into oncoprotection

“…Phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling has also been shown to be a target for the inhibition of EMT processes [15]. Akt inhibitors, such as phosphatidylinositol ether lipid analogs, have been shown to promote MET in squamous cell carcinomas of the oral cavity [24]. Rapamycin has also been proposed to hinder EMT based on its inhibitory effects on mTOR [15].…”