β-Arrestin 1 has an essential role in neurokinin-1 receptor-mediated glioblastoma cell proliferation and G2/M phase transition
| Autor: | Xiaoyun Song, Xiaofang Li, Jingyi Li, Yixin Zhang, Xiaokang Miao, Wenle Yang, Xiao-Wei Zhang, Tian-Xiong Zhou, Rui Wang, Hui Hu, Lingyun Mou, Guo-Qiang Yuan |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cyclin-dependent kinase 1 Cell growth Cell Biology Cell cycle Biology Biochemistry Cell biology Intracellular signal transduction 03 medical and health sciences 030104 developmental biology Cyclin-dependent kinase biology.protein Signal transduction Cyclin B1 Molecular Biology Protein kinase B |
| Zdroj: | Journal of Biological Chemistry. 292:8933-8947 |
| ISSN: | 0021-9258 |
| Popis: | Glioblastoma is the most common malignant brain tumor and has a poor prognosis. Tachykinin receptor neurokinin-1 (NK1R) is a promising target in glioblastoma therapy because of its overexpression in human glioblastoma. NK1R agonists promote glioblastoma cell growth, whereas NK1R antagonists efficiently inhibit cell growth both in vitro and in vivo. However, the molecular mechanisms involved in these effects are incompletely understood. β-Arrestins (ARRBs) serve as scaffold proteins and adapters to mediate intracellular signal transduction. Here we show that the ARRB1-mediated signaling pathway is essential for NK1-mediated glioblastoma cell proliferation. ARRB1 knockdown significantly inhibited NK1-mediated glioblastoma cell proliferation and induced G2/M phase cell cycle arrest. ARRB1 knockdown cells showed remarkable down-regulation of CDC25C/CDK1/cyclin B1 activity. We also demonstrated that ARRB1 mediated prolonged phosphorylation of ERK1/2 and Akt in glioblastoma cells induced by NK1R activation. ERK1/2 and Akt phosphorylation are involved in regulating CDC25C/CDK1/cyclin B1 activity. The lack of long-term ERK1/2 and Akt activation in ARRB1 knockdown cells was at least partly responsible for the delayed cell cycle progression and proliferation. Moreover, we found that ARRB1-mediated ERK1/2 and Akt phosphorylation regulated the transcriptional activity of both NF-κB and AP-1, which were involved in cyclin B1 expression. ARRB1 deficiency increased the sensitivity of glioblastoma cells to the treatment of NK1R antagonists. Taken together, our results suggest that ARRB1 plays an essential role in NK1R-mediated cell proliferation and G2/M transition in glioblastoma cells. Interference with ARRB1-mediated signaling via NK1R may have potential significance for therapeutic strategies targeting glioblastoma. |
| Databáze: | OpenAIRE |
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