The activation of c-Jun NH2-terminal kinase is required for dihydroartemisinin-induced autophagy in pancreatic cancer cells

Chen, Zhangjian; Kong, Rui; Ma, Zongwen; Han, Bing; Wang, Yongwei; Pan, Shangha; Li, Yinghua; Sun, Bei

doi:10.1186/1756-9966-33-8

Cited by 63 publications

(54 citation statements)

References 48 publications

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“…In the ovarian cancer cells, autophagy was also activated by DHA via the mTOR pathway, although the association between apoptosis and autophagy was not proven30. JNK-mediated Beclin 1 expression was demonstrated to be involved in the DHA-induced autophagic activation in human pancreatic cancer cell lines31. Autophagy controlling cellular homeostasis has been found to inhibit catabolism and inflammation in cells under stress.…”

Section: Discussionmentioning

confidence: 99%

Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway

Jiang

Meng

Lee

et al. 2016

Sci Rep

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Osteoarthritis is a disease with inflammatory and catabolic imbalance in cartilage. Dihydroartemisinin (DHA), a natural and safe anti-malarial agent, has been reported to inhibit inflammation, but its effects on chondrocytes have yet to be elucidated. We investigated the effects of DHA on catabolism in chondrocytes. Viability of SD rats chondrocytes was analyzed. Autophagy levels were determined via expression of autophagic markers LC3 and ATG5, GFP-LC3 analysis, acridine orange staining, and electron microscopy. ATG5 siRNA induced autophagic inhibition. Catabolic gene and chemokine expression was evaluated using qPCR. The NF-κB inhibitor SM7368 and p65 over-expression were used to analyze the role of NF-κB pathway in autophagic activation. A concentration of 1 μM DHA without cytotoxicity increased LC3-II and ATG5 levels as well as autophagosomal numbers in chondrocytes. DHA inhibited TNF-α-induced expression of MMP-3 and -9, ADAMTS5, CCL-2 and -5, and CXCL1, which was reversed by autophagic inhibition. TNF-α-stimulated nuclear translocation and degradation of the p65 and IκBα proteins, respectively, were attenuated in DHA-treated chondrocytes. NF-κB inhibition activated autophagy in TNF-α-treated chondrocytes, but p65 over-expression reduced the autophagic response to DHA. These results indicate that DHA might suppress the levels of catabolic and inflammatory factors in chondrocytes by promoting autophagy via NF-κB pathway inhibition.

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Section: Discussionmentioning

confidence: 99%

Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway

Jiang

Meng

Lee

et al. 2016

Sci Rep

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“…In addition, JNK/SAPK activation is considered an important apoptosis-inducing factor that exerts proapoptotic effects on apoptosis of cancer cells (36,37). Previous studies have indicated that JNK/SAPK activation results in an increase in the number of apoptotic cells in response to several anticancer agents in pancreatic cancer (38,39). The present study demonstrated that treatment with moscatilin induced sustained activation of JNK/SAPK, and the phosphorylation of JNK/SAPK was dependent on ROS generation, which was prevented by treatment with the ROS scavenger NAC.…”

Section: Discussionmentioning

confidence: 99%

Moscatilin induces apoptosis of pancreatic cancer cells via reactive oxygen species and the JNK/SAPK pathway

Zhang

Fang

et al. 2017

Molecular Medicine Reports

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Moscatilin is a bibenzyl derivative extracted from the Dendrobium aurantiacum var. denneanum, which has traditionally been used as an immunomodulatory treatment in China. The present study was designed to determine whether moscatilin is a pro-apoptotic agent in pancreatic cancer, and to elucidate the underlying mechanisms. The apoptotic and anti-proliferative effects of moscatilin on pancreatic cancer cells were determined in vitro using biochemical assays, such as the MTT assay, colony formation assay, Hoechst staining and DNA fragmentation assay, and in vivo using Panc-1 pancreatic cancer xenografts. Western blotting was also conducted to evaluate the expression levels of B-cell lymphoma 2 (Bcl2), Bcl2-associated X protein (Bax), Bcl2 homologous antagonist killer (Bak), caspase 3, cleaved-caspase 3, poly (ADP-ribose) polymerase, p-c-Jun N-terminal kinase (JNK)/stress-activated protein kinases (SAPK) and JNK/SAPK in response to moscatilin. We used DCFH-DA to detect the production of reactive oxygen species (ROS) induced by moscatilin. The present study demonstrated that moscatilin markedly inhibited pancreatic cancer cell viability and induced cell apoptosis in a concentration-dependent manner. Conversely, moscatilin did not affect the cell viability of human umbilical vein endothelial cells at the comparable dosage. Treatment with moscatilin suppressed clonogenicity of Panc-1 cells in a concentration-dependent manner. Furthermore, a decrease in Bcl2 expression, and an increase in the expression levels of Bak and Bax, was detected following treatment with moscatilin, resulting in an increase in the proapoptotic/anti-apoptotic expression ratio (Bax/Bcl2) in Panc-1 cells. Moscatilin also induced activation of the caspase-dependent mitochondrial apoptotic pathway. In addition, moscatilin enhanced cellular ROS production and induced activation of JNKSAPK signaling pathway. Conversely, pretreatment with the ROS scavenger N-acetylcysteine or the JNK/SAPK-specific inhibitor SP600125 prevented moscatilin-mediated reductions in cell viability. Furthermore, moscatilin inhibited tumor growth in nude mice bearing Panc-1 cells, without apparent toxicity. In conclusion, these results demonstrated that moscatilin may induce pancreatic cell apoptosis, and therefore may be considered a potential therapeutic agent for the treatment of pancreatic cancer.

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“…For example, Seki et al (42) highlighted the relevant role of JNK signaling in the initiation and progression of liver cancer, and Leventaki et al (43) reported that JNK activation induces tumor cell proliferation in classical Hodgkin lymphoma. Jia et al (44) reported that the activation of JNK contributes to dihydroartemisinin-induced autophagy in pancreatic cancer cells, and Shi et al (45) suggested that JNK enhances the tumor suppressive role of p53 and promotes apoptosis in several cell cancer lines, including colon, breast carcinoma and osteosarcoma.…”

Section: Discussionmentioning

confidence: 99%

JNK1/2 expression and modulation of STAT3 signaling in oral cancer

et al. 2016

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Abstract. Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that link extracellular stimuli with intracellular responses and participate in numerous cellular processes such as growth, proliferation, differentiation, inflammation and apoptosis. Persistent activation of signal transducer and activator of transcription 3 (STAT3), which is accompanied by increases in STAT3 tyrosine phosphorylation, is associated with cell proliferation, differentiation and apoptosis in oral squamous cell carcinoma (OSCC). The role and significance of the activation of MAPKs, particularly of c-Jun N-terminal kinase (JNK), on STAT3 signaling in OSCC have not been thoroughly investigated. The present study examines the effects of JNK1/2 modulation on STAT3 signaling and cellular activities in OSCC cells. The expression levels of STAT3 [total, tyrosine phosphorylated (p-Tyr) and serine phosphorylated (p-Ser)], JNK, c-Jun and cyclin D1 were assessed in the OSCC cell lines SCC25 and SCC9. Inhibition of JNK1/2 was achieved by pharmacological agents (SP600125) and by small interfering RNA (siRNA) silencing, while JNK1/2 was induced by active MAPK kinase 7. Cell proliferation and viability rates were also evaluated. Inhibition of JNK1/2 with either SP600125 treatment or specific siRNA silencing resulted in decreased levels of p-Ser STAT3 and increased levels of p-Tyr STAT3 and cyclin D1 in both cell lines. Furthermore, JNK1/2 inhibition resulted in a dose-dependent increase in cell growth and viability in both cell lines. Opposite results were observed with JNK1/2 induction in both cell lines. The present results are supportive of a potential tumor suppressive role of JNK1/2 signaling in OSCC, which may be mediated through negative crosstalk with the oncogenic STAT3 signaling pathway. The possible therapeutic implications of JNK1/2 inhibition for patients with OSCC require to be investigated.

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The activation of c-Jun NH2-terminal kinase is required for dihydroartemisinin-induced autophagy in pancreatic cancer cells

Cited by 63 publications

References 48 publications

Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway

Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway

Moscatilin induces apoptosis of pancreatic cancer cells via reactive oxygen species and the JNK/SAPK pathway

JNK1/2 expression and modulation of STAT3 signaling in oral cancer

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