Mitochondrial ROS activates ERK/autophagy pathway as a protected mechanism against deoxypodophyllotoxin-induced apoptosis

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.

An Interplay between Senescence, Apoptosis and Autophagy in Glioblastoma Multiforme—Role in Pathogenesis and Therapeutic Perspective

“…Cellular senescence is associated with the production of usually harmful cellular species, which can be cleared by autophagy, a process of removal of damaged or no longer needed cellular products [ 6 ]. In general, autophagy can help a cell to cope with many kinds of stress and cancer cells can use it to promote their intensive proliferation when their access to nutritional compounds is limited and to survive some therapies [ 7 , 8 , 9 , 10 ]. However, massive autophagy, which can lead to destructive cell “self-eating”, can induce apoptosis as suggested by the studies in which inhibition of autophagy decreased apoptosis [ 11 ].…”

Induction of apoptotic but not autophagic cell death by Cinnamomum cassia extracts on human oral cancer cells

“…During autophagy, autophagosomes form and fuse with lysosomes in the cytoplasm to degrade and recycle damaged organelles. Some proteins, such as LC3‐I, Atg, and Becline‐1 are expressed to facilitate this process (S. H. Kim et al, ). In our study, acridine orange‐stained AVOs and MDC‐stained autophagosomes strongly increased after CCE treatment (Figure ).…”

Sinoporphyrin Sodium-Mediated Sonodynamic Therapy Inhibits RIP3 Expression and Induces Apoptosis in the H446 Small Cell Lung Cancer Cell Line

“…Two major apoptosis pathways, i.e., extrinsic (mediated by death receptors) and intrinsic (mitochondrial), have been distinguished [33]. Mitochondria play an essential role in the induction of apoptosis by activating a variety of apoptosis-associated molecules that initiate the cascade of caspase activation [34]. Therefore, we performed a subsequent study to investigate changes of MMP in H446 cells exposed to DVDMS-SDT.…”