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Cordycepin promotes apoptosis by modulating the ERK-JNK signaling pathway via DUSP5 in renal cancer cells.

ABSTRACT: Constitutive activation of extracellular signal regulated kinase (ERK)-Jun NH2-terminal kinase (JNK) signaling commonly occurs in tumors. The activation of ERK promotes cell proliferation, whereas that of JNK induces cell apoptosis. However, the apoptotic mechanism of ERK-JNK signaling in cancer is not well understood. Recently, we identified that apoptosis and activation of the JNK signaling pathway were induced after cordycepin treatment in human renal cancer, suggesting that JNK signaling might contribute to TK-10 cell apoptosis. We investigated the apoptotic effects of cordycepin by evaluating the activation of the ERK-JNK signaling pathway in renal cancer TK-10 cells. We found that cordycepin downregulated ERK and DUSP5, upregulated phosphorylated-JNK (p-JNK), and induced apoptosis. Moreover, we showed that siRNA-mediated inhibition of ERK downregulated DUSP5, whereas ERK overexpression upregulated DUSP5, and that DUSP5 knockdown by siRNA upregulated p-JNK. The JNK-specific inhibitor SP600125 upregulated nuclear translocation of ?-catenin, and downregulated Dickkopf-1 (Dkk1), which has been shown to be a potent inhibitor of Wnt signaling. Dkk1 knockdown by siRNA upregulated nuclear ?-catenin, suggesting the involvement of the Wnt/?-catenin signaling pathway. DUSP5 overexpression in TK-10 cells decreased p-JNK and increased nuclear ?-catenin. The decreased Bax activation markedly protected against cordycepin-induced apoptosis. Bax subfamily proteins induced apoptosis through caspase-3. Taken together, we show that JNK signaling activation by cordycepin mediated ERK inhibition, which might have induced Bax translocation and caspase-3 activation via regulation of DUSP5 in TK-10 cells, thereby promoting the apoptosis of TK-10 cells. Targeting ERK-JNK signaling via the apoptotic effects of cordycepin could be a potential therapeutic strategy to treat renal cancer.

SUBMITTER: Hwang JH

PROVIDER: S-EPMC5004077 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Cordycepin promotes apoptosis by modulating the ERK-JNK signaling pathway via DUSP5 in renal cancer cells.

Hwang Jung-Hoo JH Joo Jong Cheon JC Kim Dae Joon DJ Jo Eunbi E Yoo Hwa-Seung HS Lee Kyung-Bok KB Park Soo Jung SJ Jang Ik-Soon IS

American journal of cancer research 20160801 8

Constitutive activation of extracellular signal regulated kinase (ERK)-Jun NH2-terminal kinase (JNK) signaling commonly occurs in tumors. The activation of ERK promotes cell proliferation, whereas that of JNK induces cell apoptosis. However, the apoptotic mechanism of ERK-JNK signaling in cancer is not well understood. Recently, we identified that apoptosis and activation of the JNK signaling pathway were induced after cordycepin treatment in human renal cancer, suggesting that JNK signaling mig ...[more]

PMID: 27648363

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Project description:PURPOSE:In recent years, understanding of the role of asparaginyl endopeptidase (AEP) in tumorigenesis has steadily increased. In this study, we investigated whether AEP expression correlates with sensitivity to chemotherapeutic drugs in gastric cancer and explored the mechanism. PATIENTS AND METHODS:AEP expression in the serum of patients' peripheral blood was measured by enzyme-linked immunosorbent assay. Patient survival time was evaluated using univariate and multivariate analyses. Mass spectrometry and co-immunoprecipitation assays were utilized to discover proteins that interact with AEP. Gastric cancer cell lines were established, in which AEP was overexpressed or knocked out using lentiviral CRISPR. The proliferative abilities of these cell lines in response to chemotherapy agents were evaluated using the Cell Counting Kit-8 method. Gene expression changes in these lines were assessed by real-time polymerase chain reaction and Western blot. RESULTS:Patients with low expression of AEP were significantly more likely to have a good prognosis and experience complete response or partial response after treatment with docetaxel/S-1 regimen. Mass spectrum analysis showed that several proteins in the focal adhesion and mitogen-activated protein kinase signaling pathways interacted with AEP. IQGAP1 was confirmed to be one of the proteins interacting with AEP, and its protein level increased when AEP was knocked out. AEP knockout decreased resistance to microtubule inhibitors, including paclitaxel, docetaxel, and T-DM1. The expression levels of MDR1, p-EGFR, p-JNK, p-ERK, and p-Rac1/cdc42 were decreased in AEP knockout gastric cancer cell lines, and inhibitors of both JNK and ERK could block AEP-induced expression of MDR1. CONCLUSION:AEP was not only a prognostic factor but also a predictive marker. AEP knockout could inhibit the activity of the EGFR/JNK/ERK signaling pathway and improve sensitivity to microtubule inhibitors through interacting with IQGAP1.

Dataset Information

Cordycepin promotes apoptosis by modulating the ERK-JNK signaling pathway via DUSP5 in renal cancer cells.

Publications

Cordycepin promotes apoptosis by modulating the ERK-JNK signaling pathway via DUSP5 in renal cancer cells.

Similar Datasets

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