Knockdown of beta-catenin controls both apoptotic and autophagic cell death through LKB1/AMPK signaling in head and neck squamous cell carcinoma cell lines

Abstract

The Wnt/beta-catenin pathway regulates the viability and radiosensitivity of head and neck squamous cancer cells (HNSCC). Increased beta-catenin predisposes HNSCC patients to poor prognosis and survival. This study was conducted to determine the mechanism by which beta-catenin regulates the viability of HNSCC. AMC-HN-3, -HN-8, UM-SCC-38, and -SCC-47 cells, which were established from human head and neck cancer specimens, and underwent cell death following beta-catenin silencing. beta-Catenin silencing significantly induced G1 arrest and increased the expression of Bax and active caspase-3, which demonstrates the sequential activation of apoptotic cascades following treatment of HNSCC with targeted siRNA. Intriguingly, beta-catenin silencing also induced autophagy. Here, we confirm that the number of autophagic vacuoles and the expression of type II light chain 3 were increased in cells that were treated with beta-catenin siRNA. These cell death modes are most likely due to the activation of LKB1-dependent AMPK following beta-catenin silencing. The activated LKB1/AMPK pathway in AMC-HN-3 cells caused G1 arrest by phosphorylating p53 and suppressing mTOR signaling. In addition, treating AMC-HN-3 cells with LKB1 siRNA preserved cell viability against beta-catenin silencing-induced cytotoxicity. Taken together, these results imply that following beta-catenin silencing, HNSCC undergo both apoptotic and autophagic cell death that are under the control of LKB1/AMPK. To the best of our knowledge, these results suggest for the first time that novel crosstalk between beta-catenin and the LKB1/AMPK pathway regulates the viability of HNSCC. This study thus presents new insights into our understanding of the cellular and molecular mechanisms involved in beta-catenin silencing-induced cell death. (C) 2012 Elsevier Inc. All rights reserved.