Buparlisib induces eukaryotic elongation factor-2 expression to cause treatment failure for lung cancer cells.

backgroundThe phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway is closely associated with the development and progression of lung cancer. Buparlisib (BKM‑120), a selective PI3K inhibitor, represents a novel potential therapeutic strategy for lung cancer. However, the reason for its limited initial efficacy as a monotherapy remains poorly understood. This study aims to systematically elucidate the key molecular mechanisms underlying the inefficacy of Buparlisib in lung cancer cells and to identify the core regulatory factors and signaling pathways involved.

methodsA549 lung cancer cells served as the primary model, along with clinical lung cancer tissue samples and nude mouse subcutaneous xenograft models. Techniques including immunohistochemistry, Western blot, flow cytometry, eukaryotic elongation factor‑2 (EEF2) knockdown (short hairpin RNA targeting EEF2 [sh‑EEF2]), Cell Counting Kit‑8 cell proliferation assays, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis analysis were used to investigate changes in the PI3K/AKT/mTOR‑EEF2 kinase (EEF2K)‑EEF2 pathway after Buparlisib treatment, to examine the relationship between reactive oxygen species (ROS) and EEF2 expression, and to evaluate the regulatory role of EEF2 in the anti‑lung‑cancer effects of Buparlisib.

resultsPI3K, EEF2K, and EEF2 were highly expressed in lung cancer tissues. Buparlisib effectively inhibited the activity of the PI3K/AKT/mTOR pathway in A549 cells, reduced EEF2K phosphorylation levels, and simultaneously significantly upregulated EEF2 protein expression (without altering its non‑phosphorylated state). EEF2 expression was highly sensitive to changes in ROS levels. Following EEF2 knockdown, the inhibitory effect of Buparlisib on A549 cell proliferation was significantly enhanced, and the apoptosis rate increased markedly. Animal experiments further confirmed that limiting EEF2 expression significantly improved the therapeutic efficacy of Buparlisib against lung cancer xenografts.

conclusionBuparlisib regulates EEF2 through a dual mechanism: directly inhibiting the PI3K/AKT/mTOR‑EEF2K pathway, thereby activating EEF2, and inducing ROS to upregulate EEF2 expression. These combined actions enhance the anti‑apoptotic function of EEF2, thereby compromising the anti‑tumor effects of Buparlisib. This study provides a new direction for optimizing PI3K inhibitor‑based treatment strategies in clinical practice.