Molecular mechanistic studies of stevioside in pancreatic cancer

Pancreatic cancer is a highly aggressive malignant tumor that is characterized by poor diagnosis and a 5-year survival rate. In 2020, according to GLOBOCAN pancreatic cancer is the seventh leading cause of cancer-related deaths with which 6 of every 100,000 people died because of pancreatic cancer. Enhanced glycolysis is considered the dominant alteration in tumorigenesis of pancreatic cancer; however, the promotion of metastasis requires enhanced OXPHOS in PDAC. Disruption of the energy balance might inhibit the metastatic progression of pancreatic cancer. Stevioside (ST) is a diterpene glycoside containing 3 glucose molecules and used as a zero-calorie natural sweetener. Studies have shown that ST has an effective anti-cancer activity. However, the mechanism of action for ST at the cellular level remains unclear. In this study, the molecular mechanism of stevioside in normal and cancer pancreatic ductal cells was examined. Analysis by MTS and Annexin V-PI staining showed ST-related anti-proliferative effect and apoptosis in PDAC cells, and no growth inhibitory effect was induced in normal cells. In non-metastatic Panc 02 cells, Rhodamine 123 and MitoTracker Green FM results revealed an ST-related decrease in the mitochondrial mass and inner membrane potential. ST triggered induction of the metabolic switch to glycolysis, preventing energy crisis by increasing the LDHA expression levels by 1.7-fold. Next, ST has induced energy crisis and overload in mitochondria through elevated inner membrane potential and diminished mitochondrial mass in metastatic PANC-1 cells. Cellular ATP levels decreased by 44% due to ST treatment. In contrast, ST treatment in HPNE cells triggered the elimination of defective mitochondria and increase cellular ATP levels. In conclusion, ST might be a potential therapeutic agent for the disruption of energy balance and mitochondria in pancreatic cancer progression.