Abstract
Deoxypodophyllotoxin (DPT) is a naturally occurring flavolignan isolated from Anthriscus sylvestris. Recently, it has been reported that DPT inhibits tubulin polymerization and induces G2/M cell cycle arrest followed by apoptosis through multiple cellular processes. Despite these findings, details regarding the cellular and molecular mechanisms underlying the DPT-mediated cell death have been poorly understood. To define a mechanism of DPT-mediated cell death response, we examined whether DPT activates signaling pathways for autophagy and apoptosis. We demonstrated that DPT inhibited cell viability and induced apoptosis in prostate cancer cell lines, as evidenced by a mitochondrial membrane potential and expression of apoptosis-related proteins. Reactive oxygen species (ROS), primarily generated from the mitochondria, play an important role in various cellular responses, such as apoptosis and autophagy. DPT significantly triggered mitochondrial ROS, which were detected by MitoSOX, a selective fluorescent dye of mitochondria-derived ROS. Furthermore, DPT induced autophagy through an up-regulation of autophagic biomarkers, including a conversion of microtubule-associated protein 1 light chain 3 - I (LC3-I) into LC3-II and a formation of acidic vesicular organelles. Moreover, mitochondrial ROS promoted AKT-independent autophagy and ERK signaling. The inhibition of autophagy with 3-methyladenine or LC3 knockdown enhanced DPT-induced apoptosis, suggesting that an autophagy plays a protective role in cell survival against apoptotic prostate cancer cells. Additionally, the results from an in vivo xenograft model confirmed that DPT inhibited tumor growth by regulating the apoptosis- and autophagy-related proteins.
Highlights
Apoptosis and autophagy are the two fundamental types of programmed cell death [1]
DPT inhibits cell viability and induces apoptosis in prostate cancer cells To investigate the cytotoxic effect of DPT, prostate cancer cells including PC-3 and LNCaP were treated with various concentrations of DPT for 24 and 48 h
Mitochondrial dysfunction has been shown to participate in apoptotic cell death, resulting from the release of cytochrome c and activation of caspase-9 and -3, which are the key steps in apoptosis signaling
Summary
Apoptosis and autophagy are the two fundamental types of programmed cell death [1]. Protein degradation occurs through via the formation of autophagosomes with a double membrane vesicle that sequesters a part of the cytoplasm. The formation of autophagosomes is initiated by an induction of various autophagy genes, including microtubule-associated protein 1 light chain 3 (LC3), phosphatidylinositide 3 kinase (PI3K), Beclin-1, and autophagy genes (ATG) [4]. A recent report suggested that the suppression of autophagy with ATG7 depletion inhibits this cytoprotective action of rapamycin in the human cells, in vitro [8]. The cytotoxic effect of autophagy could be explained by the direct selfdestructive potential of massive autophagy (type II cell death). The role of autophagy may depend on the agents, type of cancer, stage of tumorigenesis, and status of apoptosis in cancer cells
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