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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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2017
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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. |
format | Online Article Text |
id | pubmed-5780023 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
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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