Abstract
Backgroundc-Jun NH2-terminal kinases (JNKs) are strongly activated by a stressful cellular environment, such as chemotherapy and oxidative stress. Autophagy is a protein-degradation system in which double-membrane vacuoles called autophagosomes are formed. The autophagy-related gene Beclin 1 plays a key role in this process. We previously found that autophagy was induced by dihydroartemisinin (DHA) in pancreatic cancer cells. However, little is known about the complex relationship between ROS, JNK activation, autophagy induction, and Beclin 1 expression.MethodsCell viability and CCK-8 assays were carried out to determine the cell proliferation; small interfering RNAs (siRNAs) were used to knockdown c-Jun NH2-terminal kinases (JNK1/2) genes; western blot was performed to detect the protein expression of LC3, JNK, Beclin 1, caspase 3 and β-actin; production of intracellular ROS was analyzed using FACS flow cytometry; autophagy induction was confirmed by electron microscopy.ResultsIn the present study, we explored the role of DHA and Beclin 1 expression in autophagy. DHA-treated cells showed autophagy characteristics, and DHA also activated the JNK pathway and up-regulated the expression of Beclin 1. Conversely, blocking JNK signaling inhibited Beclin 1 up-regulation. JNK activation was found to primarily depend on reactive oxygen species (ROS) resulting from the DHA treatment. Moreover, JNK pathway inhibition and Beclin 1 silencing prevented the induction of DHA-induced autophagy.ConclusionsThese results suggest that the induction of autophagy by DHA is required for JNK-mediated Beclin 1 expression.
Highlights
Background cJun NH2-terminal kinases (JNKs) are strongly activated by a variety of stressful cellular environments, such as chemotherapy and oxidative stress, and induce growth inhibition or cell death [1,2]
These results suggest that the induction of autophagy by DHA is required for JNK-mediated Beclin 1 expression
These results indicate that DHA has a specific effect on human pancreatic cancer cell lines
Summary
Background cJun NH2-terminal kinases (JNKs) are strongly activated by a variety of stressful cellular environments, such as chemotherapy and oxidative stress, and induce growth inhibition or cell death [1,2]. JNK is a ‘stress-activated protein kinase’ and plays a Autophagy is a lysosomal pathway involved in the degradation of cytoplasmic macromolecules (such as proteins), and organelles. This process was well preserved during evolution. Some studies demonstrated that autophagy is induced by stressful conditions, such as metabolic stress, energy need, and chemotherapy [15,16]. Studies showed that autophagy promoted cancer cell survival through the generation of metabolic substrates maintaining cellular activity, thereby limiting chemotherapy cytotoxicity [19]. This study aimed to further elucidate the role of treatment-induced autophagy in pancreatic cancer cells
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