Down-regulation of malic enzyme 1 and 2: Sensitizing head and neck squamous cell carcinoma cells to therapy-induced senescence

Abstract

Background The purpose of this study was to present the results of our investigation of malic enzyme (ME) expression and the induction of senescence in head and neck squamous cell carcinoma (HNSCC). Methods P53, ME1, ME2, and aspects of cellular metabolism, such as reactive oxygen species (ROS) were investigated in HNSCC cell lines. Results Both metformin and ionizing radiation inhibited the expression of ME2, but not ME1, in HNSCC. Knockdown of ME1 or ME2 potentiated therapy-induced senescence in HNSCC cells regardless of p53 status, and led to increased p21 and generation of ROS. Therapy-induced senescence in ME-depleted cells was blocked by the antioxidant N-acetyl cysteine. Finally, high expression of ME2 was associated with poorer overall survival (OS) in patients with HNSCC. Conclusion Depletion of ME enhances therapy-induced senescence and seems driven largely by ROS. ME2 expression in HNSCC may be associated with poor outcome, providing a possible link between therapy-induced senescence and patient outcome, and indicating a potential therapeutic benefit of targeting ME2.