ABSTRACT
The Wnt/ß-catenin pathway regulates the viability and radiosensitivity of head and neck squamous cancer cells (HNSCC). Increased ß-catenin predisposes HNSCC patients to poor prognosis and survival. This study was conducted to determine the mechanism by which ß-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 ß-catenin silencing. ß-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, ß-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 ß-catenin siRNA. These cell death modes are most likely due to the activation of LKB1-dependent AMPK following ß-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 ß-catenin silencing-induced cytotoxicity. Taken together, these results imply that following ß-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 ß-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 ß-catenin silencing-induced cell death.
