β-Arrestin 1 has an essential role in neurokinin-1 receptor-mediated glioblastoma cell proliferation and G2/M phase transition.
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 bothin vitroandin vivoHowever, 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.
From the Institute of Biochemistry and Molecular Biology, School of Life Sciences and Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China and.
Yi-Xin
YX
Zhang
From the Institute of Biochemistry and Molecular Biology, School of Life Sciences and Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China and.
Xiao-Fang
XF
Li
the Department of Neurosurgery, Second Affiliated Hospital of Lanzhou University, Lanzhou 730000, China.
Guo-Qiang
GQ
Yuan
From the Institute of Biochemistry and Molecular Biology, School of Life Sciences and Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China and.
Hui
H
Hu
From the Institute of Biochemistry and Molecular Biology, School of Life Sciences and Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China and.
Xiao-Yun
XY
Song
From the Institute of Biochemistry and Molecular Biology, School of Life Sciences and Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China and.
Jing-Yi
JY
Li
From the Institute of Biochemistry and Molecular Biology, School of Life Sciences and Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China and.
Xiao-Kang
XK
Miao
From the Institute of Biochemistry and Molecular Biology, School of Life Sciences and Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China and.
Tian-Xiong
TX
Zhou
From the Institute of Biochemistry and Molecular Biology, School of Life Sciences and Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China and.
Wen-Le
WL
Yang
From the Institute of Biochemistry and Molecular Biology, School of Life Sciences and Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China and.
Xiao-Wei
XW
Zhang
From the Institute of Biochemistry and Molecular Biology, School of Life Sciences and Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China and muly@lzu.edu.cn.
Ling-Yun
LY
Mou
From the Institute of Biochemistry and Molecular Biology, School of Life Sciences and Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China and wangrui@lzu.edu.cn.
Rui
R
Wang
D016203:CDC2 Protein Kinase; D002460:Cell Line; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D016195:G2 Phase; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism*; D000071559:beta-Arrestin 1 / Q000235:genetics / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism
C000605253:ARRB1 protein, human; C534699:CCNB1 protein, human; D056744:Cyclin B1; D018040:Receptors, Neurokinin-1; D000071559:beta-Arrestin 1; D051057:Proto-Oncogene Proteins c-akt; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases
arrestin; cell cycle; cell proliferation; cyclin-dependent kinase (CDK); glioblastoma; neurokinin-1 receptor