Generic placeholder image

Current Protein & Peptide Science

Editor-in-Chief

ISSN (Print): 1389-2037
ISSN (Online): 1875-5550

Research Article

PAK1 Inhibition Suppresses the Proliferation, Migration and Invasion of Glioma Cells

Author(s): Qinghao Yi, Tianze Chen, Kunlin Zhou, Qiang Ma, Zhiyuan Sun and Hengliang Shi*

Volume 24, Issue 2, 2023

Published on: 23 January, 2023

Page: [178 - 189] Pages: 12

DOI: 10.2174/1389203724666221226150329

Price: $65

Abstract

Background: p21-activated kinase 1 (PAK1) is abnormally expressed in glioma, but its roles and mechanisms in glioma remain unclear. This study aims to explore the effects of PAK1 inhibition on the proliferation, migration and invasion of glioma cells.

Methods: Cell Counting Kit-8 (CCK-8), 5‐ethynyl‐20‐deoxyuridine (EdU) incorporation and colony formation assays were performed to evaluate the effects of PAK1 inhibition on the proliferation of glioma cells. The cell cycle distribution and apoptosis rate of glioma cells were explored by flow cytometry. Wound healing and Transwell assays were performed to investigate the effects of PAK1 inhibition on glioma cell migration and invasion. The orthotopic xenograft glioma model was used to probe the effect of PAK1 silencing on glioma tumor formation.

Results: PAK1 inhibition arrested cells at the G1 phase and induced apoptosis of glioma cells. Moreover, the knockdown of PAK1 decreased the protein expression levels of MDM2, p38, p-p38, cyclin D1, CDK4, Bcl-2, MMP2, MMP9, and cofilin but increased the protein levels of p53, Bax, p21 and cleaved caspase-3. A xenograft glioma model confirmed that the silencing of PAK1 repressed the formation of tumors induced by U87 cell transplantation.

Conclusion: This study showed that PAK1 inhibition impedes the proliferation, migration, and invasion of glioma cells.

Keywords: p21-activated kinase 1, glioma, proliferation, migration, invasion, G1 phase.

Graphical Abstract
[1]
Han, X.; Li, H.; Zhang, Y.; Qin, J.; Yang, Q.; Wang, L.; Yuan, M.; Xia, C. Brain lipid-binding protein promotes proliferation and modulates cell cycle in C6 rat glioma cells. Int. J. Oncol., 2017, 51(5), 1439-1448.
[http://dx.doi.org/10.3892/ijo.2017.4132] [PMID: 29048614]
[2]
Chen, R.; Smith-Cohn, M.; Cohen, A.L.; Colman, H. Glioma subclassifications and their clinical significance. Neurotherapeutics, 2017, 14(2), 284-297.
[http://dx.doi.org/10.1007/s13311-017-0519-x] [PMID: 28281173]
[3]
Liang, X.; Dong, Z.; Bin, W.; Dekang, N.; Xuhang, Z.; Shuyuan, Z.; Liwen, L.; Kai, J.; Caixing, S. PAX3 Promotes proliferation of human glioma cells by WNT/β-catenin signaling pathways. J. Mol. Neurosci., 2019, 68(1), 66-77.
[http://dx.doi.org/10.1007/s12031-019-01283-2] [PMID: 30826985]
[4]
Milanović D.; Firat, E.; Grosu, A.L.; Niedermann, G. Increased radiosensitivity and radiothermosensitivity of human pancreatic MIAPaCa-2 and U251 glioblastoma cell lines treated with the novel Hsp90 inhibitorNVP-HSP990. Radiat. Oncol., 2013, 8(1), 42-42.
[http://dx.doi.org/10.1186/1748-717X-8-42] [PMID: 23448094]
[5]
Feng, J.; Yan, P.F.; Zhao, H.Y.; Zhang, F.C.; Zhao, W.H.; Feng, M. SIRT6 suppresses glioma cell growth via induction of apoptosis, inhibition of oxidative stress and suppression of JAK2/STAT3 signaling pathway activation. Oncol. Rep., 2016, 35(3), 1395-1402.
[http://dx.doi.org/10.3892/or.2015.4477] [PMID: 26648570]
[6]
Janbazian, L.; Karamchandani, J.; Das, S. Mouse models of glioblastoma: Lessons learned and questions to be answered. J. Neurooncol., 2014, 118(1), 1-8.
[http://dx.doi.org/10.1007/s11060-014-1401-x] [PMID: 24522719]
[7]
Kumar, R.; Li, D.Q. PAKs in human cancer progression. Adv. Cancer Res., 2016, 130, 137-209.
[http://dx.doi.org/10.1016/bs.acr.2016.01.002] [PMID: 27037753]
[8]
Rane, C.K.; Minden, A. P21 activated kinase signaling in cancer. Semin. Cancer Biol., 2019, 54, 40-49.
[PMID: 29330094]
[9]
Rane, C.K.; Minden, A. P21 activated kinases. Small GTPases, 2014, 5(1), e28003.
[http://dx.doi.org/10.4161/sgtp.28003] [PMID: 24658305]
[10]
Radu, M.; Semenova, G.; Kosoff, R.; Chernoff, J. PAK signalling during the development and progression of cancer. Nat. Rev. Cancer, 2014, 14(1), 13-25.
[http://dx.doi.org/10.1038/nrc3645] [PMID: 24505617]
[11]
Delorme-Walker, V.D.; Peterson, J.R.; Chernoff, J.; Waterman, C.M.; Danuser, G.; DerMardirossian, C.; Bokoch, G.M. Pak1 regulates focal adhesion strength, myosin IIA distribution, and actin dynamics to optimize cell migration. J. Cell Biol., 2011, 193(7), 1289-1303.
[http://dx.doi.org/10.1083/jcb.201010059] [PMID: 21708980]
[12]
Ong, C.C.; Jubb, A.M.; Haverty, P.M.; Zhou, W.; Tran, V.; Truong, T.; Turley, H.; O’Brien, T.; Vucic, D.; Harris, A.L.; Belvin, M.; Friedman, L.S.; Blackwood, E.M.; Koeppen, H.; Hoeflich, K.P. Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells. Proc. Natl. Acad. Sci. USA, 2011, 108(17), 7177-7182.
[http://dx.doi.org/10.1073/pnas.1103350108] [PMID: 21482786]
[13]
Huang, K.; Fang, C.; Yi, K.; Liu, X.; Qi, H.; Tan, Y.; Zhou, J.; Li, Y.; Liu, M.; Zhang, Y.; Yang, J.; Zhang, J.; Li, M.; Kang, C. The role of PTRF/Cavin1 as a biomarker in both glioma and serum exosomes. Theranostics, 2018, 8(6), 1540-1557.
[http://dx.doi.org/10.7150/thno.22952] [PMID: 29556340]
[14]
Zhang, Z.; Wang, Z.; Huang, K.; Liu, Y.; Wei, C.; Zhou, J.; Zhang, W.; Wang, Q.; Liang, H.; Zhang, A.; Wang, G.; Zhen, Y.; Han, L. PLK4 is a determinant of temozolomide sensitivity through phosphorylation of IKBKE in glioblastoma. Cancer Lett., 2019, 443, 91-107.
[http://dx.doi.org/10.1016/j.canlet.2018.11.034] [PMID: 30529153]
[15]
Zheng, Q.; Han, L.; Dong, Y.; Tian, J.; Huang, W.; Liu, Z.; Jia, X.; Jiang, T.; Zhang, J.; Li, X.; Kang, C.; Ren, H. JAK2/STAT3 targeted therapy suppresses tumor invasion via disruption of the EGFRvIII/JAK2/STAT3 axis and associated focal adhesion in EGFRvIII-expressing glioblastoma. Neuro-oncol., 2014, 16(9), 1229-1243.
[http://dx.doi.org/10.1093/neuonc/nou046] [PMID: 24861878]
[16]
Chen, L.; Han, L.; Zhang, K.; Shi, Z.; Zhang, J.; Zhang, A.; Wang, Y.; Song, Y.; Li, Y.; Jiang, T.; Pu, P.; Jiang, C.; Kang, C. VHL regulates the effects of miR-23b on glioma survival and invasion via suppression of HIF-1α/VEGF and β-catenin/Tcf-4 signaling. Neuro-oncol., 2012, 14(8), 1026-1036.
[http://dx.doi.org/10.1093/neuonc/nos122] [PMID: 22649212]
[17]
Aoki, H.; Yokoyama, T.; Fujiwara, K.; Tari, A.M.; Sawaya, R.; Suki, D.; Hess, K.R.; Aldape, K.D.; Kondo, S.; Kumar, R.; Kondo, Y. Phosphorylated Pak1 level in the cytoplasm correlates with shorter survival time in patients with glioblastoma. Clin. Cancer Res., 2007, 13(22), 6603-6609.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-0145] [PMID: 18006760]
[18]
Yang, Z.; Wang, H.; Xia, L.; Oyang, L.; Zhou, Y.; Zhang, B.; Chen, X.; Luo, X.; Liao, Q.; Liang, J. Overexpression of PAK1 correlates with aberrant expression of EMT markers and poor prognosis in non-small cell lung cancer. J. Cancer, 2017, 8(8), 1484-1491.
[http://dx.doi.org/10.7150/jca.18553] [PMID: 28638464]
[19]
Al-Azayzih, A.; Gao, F.; Somanath, P.R. P21 activated kinase-1 mediates transforming growth factor β1-induced prostate cancer cell epithelial to mesenchymal transition. Biochim. Biophys. Acta Mol. Cell Res., 2015, 1853(5), 1229-1239.
[http://dx.doi.org/10.1016/j.bbamcr.2015.02.023] [PMID: 25746720]
[20]
Clevers, H. Wnt/beta-catenin signaling in development and disease. Cell, 2006, 127(3), 469-480.
[http://dx.doi.org/10.1016/j.cell.2006.10.018] [PMID: 17081971]
[21]
Zhu, M.; Xu, Y.; Zhang, W.; Gu, T.; Wang, D. Inhibition of PAK1 alleviates cerulein-induced acute pancreatitis via p38 and NF-κB pathways. Biosci. Rep., 2019, 39(3), BSR20182221.
[http://dx.doi.org/10.1042/BSR20182221]
[22]
Qing, H.; Gong, W.; Che, Y.; Wang, X.; Peng, L.; Liang, Y.; Wang, W.; Deng, Q.; Zhang, H.; Jiang, B. PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation. Tumour Biol., 2012, 33(4), 985-994.
[http://dx.doi.org/10.1007/s13277-012-0327-1] [PMID: 22252525]
[23]
Prudnikova, T.Y.; Villamar-Cruz, O.; Rawat, S.J.; Cai, K.Q.; Chernoff, J. Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells. Oncogene, 2016, 35(17), 2178-2185.
[http://dx.doi.org/10.1038/onc.2015.278] [PMID: 26257058]
[24]
Brabletz, T.; Kalluri, R.; Nieto, M.A.; Weinberg, R.A. EMT in cancer. Nat. Rev. Cancer, 2018, 18(2), 128-134.
[http://dx.doi.org/10.1038/nrc.2017.118] [PMID: 29326430]
[25]
Zhu, Y.; Zhang, X.; Wang, L.; Ji, Z.; Xie, M.; Zhou, X.; Liu, Z.; Shi, H.; Yu, R. Loss of SH3GL2 promotes the migration and invasion behaviours of glioblastoma cells through activating the STAT3/MMP2 signalling. J. Cell. Mol. Med., 2017, 21(11), 2685-2694.
[http://dx.doi.org/10.1111/jcmm.13184] [PMID: 28470949]
[26]
Zhu, H.; Chen, D.; Tang, J.; Huang, C.; Lv, S.; Wang, D.; Li, G. Overexpression of centrosomal protein 55 regulates the proliferation of glioma cell and mediates proliferation promoted by EGFRvIII in glioblastoma U251 cells. Oncol. Lett., 2018, 15(2), 2700-2706.
[PMID: 29434995]
[27]
Zhang, T.; Ji, D.; Wang, P.; Liang, D.; Jin, L.; Shi, H.; Liu, X.; Meng, Q.; Yu, R.; Gao, S. The atypical protein kinase RIOK3 contributes to glioma cell proliferation/survival, migration/invasion and the AKT/mTOR signaling pathway. Cancer Lett., 2018, 415, 151-163.
[http://dx.doi.org/10.1016/j.canlet.2017.12.010] [PMID: 29233656]
[28]
Choi, P.J.; Tubbs, R.S.; Oskouian, R.J. Emerging cellular therapies for glioblastoma multiforme. Cureus, 2018, 10(3), e2305.
[PMID: 29755901]
[29]
Yeo, D.; He, H.; Baldwin, G.; Nikfarjam, M. P-038 FRAX597, a PAK1 inhibitor, synergises with gemcitabine in the reduction of pancreatic cancer growth. Ann. Oncol., 2015, 26, iv10.
[http://dx.doi.org/10.1093/annonc/mdv233.38]
[30]
Park, J.; Kim, J.; Park, J.K.; Huang, S.; Kwak, S.Y.; Ryu, K.A.; Kong, G.; Park, J.; Koo, B.S. Association of p21-activated kinase-1 activity with aggressive tumor behavior and poor prognosis of head and neck cancer. Head Neck, 2015, 37(7), 953-963.
[http://dx.doi.org/10.1002/hed.23695] [PMID: 24634274]
[31]
Romero, L.E.A.; Cruz, O.V.; Chernoff, J. Abstract 4865: Pak1 links the Wnt/β-catenin pathway to ErbB2 signaling in breast cancer cells. Cancer Res., 2012, 72(8_Supplement)(Suppl.), 4865-4865.
[http://dx.doi.org/10.1158/1538-7445.AM2012-4865]
[32]
Wu, D.W.; Wu, T.C.; Chen, C.Y.; Lee, H. PAK1 is a novel therapeutic target in tyrosine kinase inhibitor–resistant lung adenocarcinoma activated by the PI3K/AKT signaling regardless of EGFR mutation. Clin. Cancer Res., 2016, 22(21), 5370-5382.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2724] [PMID: 27178741]
[33]
Huang, B.M. Cordycepin induced MA-10 mouse Leydig tumor cell apoptosis by regulating p38 MAPKs and PI3K/AKT signaling pathways. Free Radic. Biol. Med., 2017, 108, S32.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.131]
[34]
Zhang, Z.L.; Liu, G.; Peng, L.; Zhang, C.; Jia, Y.M.; Yang, W.H.; Mao, L. Effect of PAK1 gene silencing on proliferation and apoptosis in hepatocellular carcinoma cell lines MHCC97-H and HepG2 and cells in xenograft tumor. Gene Ther., 2018, 25(4), 284-296.
[http://dx.doi.org/10.1038/s41434-018-0016-9] [PMID: 29802374]
[35]
Bykov, V.J.N.; Eriksson, S.E.; Bianchi, J.; Wiman, K.G. Targeting mutant p53 for efficient cancer therapy. Nat. Rev. Cancer, 2018, 18(2), 89-102.
[http://dx.doi.org/10.1038/nrc.2017.109] [PMID: 29242642]
[36]
Wang, S.; Zhao, Y.; Aguilar, A.; Bernard, D.; Yang, C.Y. Targeting the MDM2–p53 protein–protein interaction for new cancer therapy: progress and challenges. Cold Spring Harb. Perspect. Med., 2017, 7(5), a026245.
[http://dx.doi.org/10.1101/cshperspect.a026245] [PMID: 28270530]
[37]
Wang, Y.; Gu, X.; Li, W.; Zhang, Q.; Zhang, C. PAK1 overexpression promotes cell proliferation in cutaneous T cell lymphoma via suppression of PUMA and p21. J. Dermatol. Sci., 2018, 90(1), 60-67.
[http://dx.doi.org/10.1016/j.jdermsci.2017.11.019] [PMID: 29307600]
[38]
Brooks, J.K.; Nikitakis, N.G.; Frankel, B.F.; Papadimitriou, J.C.; Sauk, J.J. Oral inflammatory myofibroblastic tumor demonstrating ALK, p53, MDM2, CDK4, pRb, and Ki-67 immunoreactivity in an elderly patient. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod., 2005, 99(6), 716-726.
[http://dx.doi.org/10.1016/j.tripleo.2004.11.023] [PMID: 15897859]
[39]
Xie, X.; Clausen, O.P.F.; Angelis, P.D.; Boysen, M. The prognostic value of spontaneous apoptosis, Bax, Bcl-2, and p53 in oral squamous cell carcinoma of the tongue. Cancer, 1999, 86(6), 913-920.
[http://dx.doi.org/10.1002/(SICI)1097-0142(19990915)86:6<913:AID-CNCR4>3.0.CO;2-A] [PMID: 10491515]
[40]
Wang, H.; Tao, L.; Jin, F.; Gu, H.; Dai, X.; Ni, T.; Feng, J.; Ding, Y.; Xiao, W.; Qian, Y.; Liu, Y. Cofilin 1 induces the epithelial-mesenchymal transition of gastric cancer cells by promoting cytoskeletal rearrangement. Oncotarget, 2017, 8(24), 39131-39142.
[http://dx.doi.org/10.18632/oncotarget.16608] [PMID: 28388575]
[41]
Ren, T.; Zhu, L.; Cheng, M. CXCL10 accelerates EMT and metastasis by MMP-2 in hepatocellular carcinoma. Am. J. Transl. Res., 2017, 9(6), 2824-2837.
[PMID: 28670372]
[42]
Wang, J.; Hirose, H.; Du, G.; Chong, K.; Kiyohara, E.; Witz, I.P.; Hoon, D.S.B. P-REX1 amplification promotes progression of cutaneous melanoma via the PAK1/P38/MMP-2 pathway. Cancer Lett., 2017, 407, 66-75.
[http://dx.doi.org/10.1016/j.canlet.2017.08.001] [PMID: 28803992]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy