Keratins are epithelial-specific intermediate filament (IF) proteins, which are expressed in a tissue-specific manner. As part of the cytoskeleton, keratins are important for the mechanical stability and integrity of epithelial cells and tissues. Moreover, a number of keratins are involved in intracellular signalling pathways which regulate the response to injuries and nonmechanical stresses, cell growth, cell death and cancer progression. Expression of keratins is maintained during malignant transformation of simple epithelial cells. However, vimentin, a mesenchymal-specific IF, is often co-expressed with keratins in late-stage cancer cells presenting a dedifferentiated phenotype. This is associated with an increased metastatic potential. Metastasis, the foremost cause of mortality in cancer patients, is a coordinated biological process involving multiple intracellular signalling pathways. PI3K/Akt pathway has been shown to play a role in invasion/metastasis. Moreover, the three Akt isoforms would play differential roles in this process. In the present study, we investigate the role of Akt isoforms in regulating the expression of keratins and vimentin in different epithelial carcinoma cell lines and the implication of IF in Akt-regulated cell invasion. Our results show that overexpression of constitutively active Akt isoforms up-regulates IF protein and mRNA levels, by increasing IF mRNA stability. On the contrary, down-regulation of Akt isoforms by shRNA decreases IF protein levels. To examine the regulation of IF expression under a more physiological condition, we treated cells with TGF-b1, which is known to induce Akt activation. We demonstrated that IF are up-regulated by TGF-b1 in PI3K-dependent manner. To our knowledge, these results represent the first indication that Akt activity is regulating IF expression. Overexpression of Akt isoforms also increases in vitro cell invasion. Interestingly, we showed that down-regulation of vimentin by siRNA decreases Akt2-induced cell invasion. These results support the hypothesis that modulation of IF expression plays an active role in cancer progression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 994.