Abstract
Laryngeal squamous cell carcinoma (LSCC) is a prevalent head and neck neoplasm with escalating global morbidity and mortality rates. Despite the increasing burden of LSCC, the drugs currently approved for its treatment are limited. Therefore, it is necessary to identify novel and promising drugs that target LSCC. Cucurbitacin E (CuE) is a naturally oxygenated tetracyclic triterpenoid that suppresses several cancers. However, its anti-LSCC activity and the molecular mechanisms of action remain unclear. This study explored its impact on LSCC, revealing cell viability attenuation and apoptosis enhancement in vitro. Further investigations indicated that CuE significantly decreased mitochondrial membrane potential, thereby promoting cytochrome c release, increasing cleaved-Caspase 3 and cleaved-PARP levels, and triggering mitochondria-dependent apoptosis. Concurrently, exposure of LSCC cells to CuE enhanced endoplasmic reticulum (ER) stress, mobilized the protein kinase RNA-like endoplasmic reticulum kinase/initiation factor 2a/ATF4/C-EBP homologous protein pathway, and induced LSCC cell apoptosis. Finally, CuE markedly elevated intracellular reactive oxygen species (ROS) levels. When ROS were eliminated with N-acetylcysteine, CuE-mediated mitochondrial dysfunction, ER stress, and cell apoptosis were nearly abolished. Similar outcomes were observed in murine LSCC models. Together, these results highlight that CuE suppresses proliferation while triggering apoptosis in LSCC cells via ROS-regulated mitochondrial dysfunction and the ER stress pathway. Hence, CuE may serve as a promising candidate for LCSS treatment.