Abstract
Pancreatic cancer (PC) is one of the most lethal diseases, and effective treatment of PC patients remains an enormous challenge. Rocaglamide A (Roc-A), a bioactive molecule extracted from the plant Aglaia elliptifolia, has aroused considerable attention as a therapeutic choice for numerous cancer treatments. Nevertheless, the effects and underlying mechanism of Roc-A in PC are still poorly understood. Here, we found that Roc-A inhibited growth and stimulated apoptosis by induction of mitochondria dysfunction in PC. Moreover, Roc-A accelerated autophagosome synthesis and triggered mitophagy involving the PTEN-induced putative kinase 1 (PINK1)/Parkin signal pathway. We also demonstrated that inhibition of autophagy/mitophagy can sensitize PC cells to Roc-A. Finally, Roc-A treatment results in an obvious accumulation of reactive oxygen species (ROS), and pretreatment of cells with the reactive oxygen species scavenger N-acetylcysteine reversed the apoptosis and autophagy/mitophagy induced by Roc-A. Together, our results elucidate the potential mechanisms of action of Roc-A. Our findings indicate Roc-A as a potential therapeutic agent against PC and suggest that combination inhibition of autophagy/mitophagy may be a promising therapeutic strategy in PC.
Highlights
Pancreatic cancer (PC) is a lethal disease
These results demonstrated that Rocaglamide A (Roc-A)-induced PC cell apoptosis and autophagy/mitophagy were mediated by reactive oxygen species (ROS)
Our data demonstrated that Roc-A induces mitophagy by the PINK1/Parkin signal pathway and provokes PC cell apoptosis by generation of intracellular ROS, loss of the Δψm, and release of cytochrome c
Summary
Pancreatic cancer (PC) is a lethal disease. Curative resection is the first to consider for early-stage patients, but 5-year survival is only up to 25% (Kamisawa et al, 2016, Deplanque and Demartines, 2017). Autophagy can be activated in response to a number of stressors including cancer chemotherapeutics, facilitating cell survival and leading to treatment resistance. Mitophagy is a specific type of autophagy in which impaired mitochondria are specially targeted for degradation to promote mitochondrial turnover and maintain cellular homeostasis (Drake et al, 2017). Several reports showed that mitophagy is involved in tumor resistance to various cancer therapies by removing damaged mitochondria and maintaining healthy and functional mitochondria (Pickles et al, 2018). Our data demonstrated that Roc-A provokes PC cell apoptosis by induction of mitochondria dysfunction while activating PINK1/Parkin-mediated protective mitophagy. These findings demonstrate a novel relationship between Roc-A and mitophagy, which is of particular guidance for a potential strategy for PC treatment
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