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Signalling pathways in pancreatic cancer and its treatment by targeting of mitochondria
Ezrová, Zuzana ; Neužil, Jiří (advisor) ; Masařík, Michal (referee) ; Divoký, Vladimír (referee)
Pancreatic cancer is one of the deadliest types of malignant diseases. Asymptomatic early tumour stages, tumour heterogeneity, cancer cell plasticity and unusually dense pancreatic stroma are responsible for the poor prognosis attributed to late diagnosis and therapy resistance. Therefore, targeting of a pivotal element common for any cell type within the tumour, e.g. mitochondria, may bring significant improvement. In this work, we demonstrate mitochondrial targeting of metformin, an anti-diabetic drug associated with reduced risk of developing pancreatic cancer, substantially increases accumulation of the compound in mitochondria. In consequence, we show that mitochondrially targeted metformin, MitoMet, eliminates pancreatic cancer cells in more than 1000-fold lower concentration than used for its parental compound. Following interaction with respiratory complex I (CI), MitoMet inhibits mitochondrial respiration, activates AMP-activated protein kinase pathway and causes depolarization of mitochondrial membrane potential in pancreatic cancer cells. Moreover, MitoMet induces cell cycle arrest and apoptosis, which is partially mediated via increased level of reactive oxygen species (ROS), and suppresses pancreatic tumour growth in vivo. Interestingly, SMAD4-deficient pancreatic cancer cells manifest...
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