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Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4

Neuroblastoma is the most common extracranial solid childhood tumor. Despite the availability of advanced multimodal therapy, high-risk patients still have low survival rates. p21-activated kinase 4 (PAK4) has been shown to regulate many cellular processes in cancer cells, including migration, polar...

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Autores principales: Li, Zhiheng, Li, Xiaolu, Xu, Lixiao, Tao, Yanfang, Yang, Chun, Chen, Xiaolan, Fang, Fang, Wu, Yi, Ding, Xin, Zhao, He, Li, Mei, Qian, Guanghui, Xu, Yunyun, Ren, Junli, Du, Weiwei, Wang, Jian, Lu, Jun, Hu, Shaoyan, Pan, Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780023/
https://www.ncbi.nlm.nih.gov/pubmed/29048629
http://dx.doi.org/10.3892/or.2017.5989
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author Li, Zhiheng
Li, Xiaolu
Xu, Lixiao
Tao, Yanfang
Yang, Chun
Chen, Xiaolan
Fang, Fang
Wu, Yi
Ding, Xin
Zhao, He
Li, Mei
Qian, Guanghui
Xu, Yunyun
Ren, Junli
Du, Weiwei
Wang, Jian
Lu, Jun
Hu, Shaoyan
Pan, Jian
author_facet Li, Zhiheng
Li, Xiaolu
Xu, Lixiao
Tao, Yanfang
Yang, Chun
Chen, Xiaolan
Fang, Fang
Wu, Yi
Ding, Xin
Zhao, He
Li, Mei
Qian, Guanghui
Xu, Yunyun
Ren, Junli
Du, Weiwei
Wang, Jian
Lu, Jun
Hu, Shaoyan
Pan, Jian
author_sort Li, Zhiheng
collection PubMed
description Neuroblastoma is the most common extracranial solid childhood tumor. Despite the availability of advanced multimodal therapy, high-risk patients still have low survival rates. p21-activated kinase 4 (PAK4) has been shown to regulate many cellular processes in cancer cells, including migration, polarization and proliferation. However, the role of PAK4 in neuroblastoma remains unclear. In the present study, we demonstrated that PAK4 was overexpressed in neuroblastoma tissues and was correlated with tumor malignance and prognosis. To investigate the function of PAK4 in neuroblastoma, we used a small-molecule inhibitor that targets PAK4, that is, PF-3758309. Our results showed that PF-3758309 significantly induced cell cycle arrest at the G1 phase and apoptosis in neuroblastoma cell lines. Meanwhile, the inhibition of PAK4 by PF-3758309 increased the expression of CDKN1A, BAD and BAK1 and decreased the expression of Bcl-2 and Bax. In addition, we screened the target genes of PAK4 by PCR array and found that 23 genes were upregulated (including TP53I3, TBX3, EEF1A2, CDKN1A, IFNB1 and MAPK8IP2) and 20 genes were downregulated (including TNFSF8, Bcl2-A1, Bcl2L1, SOCS3, BIRC3 and NFKB1) after PAK4 inhibition by PF-3758309. Moreover, PAK4 was found to regulate the cell cycle and apoptosis via the ERK signaling pathway. In conclusion, the present study demonstrated, for the first time, the expression and function of PAK4 in neuroblastomas and the inhibitory effect of PF-3758309, which deserves further investigation as an alternative strategy for neuroblastoma treatment.
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spelling pubmed-57800232018-02-12 Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4 Li, Zhiheng Li, Xiaolu Xu, Lixiao Tao, Yanfang Yang, Chun Chen, Xiaolan Fang, Fang Wu, Yi Ding, Xin Zhao, He Li, Mei Qian, Guanghui Xu, Yunyun Ren, Junli Du, Weiwei Wang, Jian Lu, Jun Hu, Shaoyan Pan, Jian Oncol Rep Articles Neuroblastoma is the most common extracranial solid childhood tumor. Despite the availability of advanced multimodal therapy, high-risk patients still have low survival rates. p21-activated kinase 4 (PAK4) has been shown to regulate many cellular processes in cancer cells, including migration, polarization and proliferation. However, the role of PAK4 in neuroblastoma remains unclear. In the present study, we demonstrated that PAK4 was overexpressed in neuroblastoma tissues and was correlated with tumor malignance and prognosis. To investigate the function of PAK4 in neuroblastoma, we used a small-molecule inhibitor that targets PAK4, that is, PF-3758309. Our results showed that PF-3758309 significantly induced cell cycle arrest at the G1 phase and apoptosis in neuroblastoma cell lines. Meanwhile, the inhibition of PAK4 by PF-3758309 increased the expression of CDKN1A, BAD and BAK1 and decreased the expression of Bcl-2 and Bax. In addition, we screened the target genes of PAK4 by PCR array and found that 23 genes were upregulated (including TP53I3, TBX3, EEF1A2, CDKN1A, IFNB1 and MAPK8IP2) and 20 genes were downregulated (including TNFSF8, Bcl2-A1, Bcl2L1, SOCS3, BIRC3 and NFKB1) after PAK4 inhibition by PF-3758309. Moreover, PAK4 was found to regulate the cell cycle and apoptosis via the ERK signaling pathway. In conclusion, the present study demonstrated, for the first time, the expression and function of PAK4 in neuroblastomas and the inhibitory effect of PF-3758309, which deserves further investigation as an alternative strategy for neuroblastoma treatment. D.A. Spandidos 2017-11 2017-09-22 /pmc/articles/PMC5780023/ /pubmed/29048629 http://dx.doi.org/10.3892/or.2017.5989 Text en Copyright: © Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Li, Zhiheng
Li, Xiaolu
Xu, Lixiao
Tao, Yanfang
Yang, Chun
Chen, Xiaolan
Fang, Fang
Wu, Yi
Ding, Xin
Zhao, He
Li, Mei
Qian, Guanghui
Xu, Yunyun
Ren, Junli
Du, Weiwei
Wang, Jian
Lu, Jun
Hu, Shaoyan
Pan, Jian
Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4
title Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4
title_full Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4
title_fullStr Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4
title_full_unstemmed Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4
title_short Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4
title_sort inhibition of neuroblastoma proliferation by pf-3758309, a small-molecule inhibitor that targets p21-activated kinase 4
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780023/
https://www.ncbi.nlm.nih.gov/pubmed/29048629
http://dx.doi.org/10.3892/or.2017.5989
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