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Combination of lentivirus-mediated silencing of PPM1D and temozolomide chemotherapy eradicates malignant glioma through cell apoptosis and cell cycle arrest

  • Authors:
    • Peng Wang
    • Jing-An Ye
    • Chong-Xian Hou
    • Dong Zhou
    • Sheng-Quan Zhan
  • View Affiliations / Copyright

    Affiliations: Department of Neurosurgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 2544-2552
    |
    Published online on: September 14, 2016
       https://doi.org/10.3892/or.2016.5089
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Abstract

Temozolomide (TMZ) is approved for use as first-line treatment for glioblastoma multiforme (GBM). However, GBM shows chemoresistance shortly after the initiation of treatment. In order to detect whether silencing of human protein phosphatase 1D magnesium dependent (PPM1D) gene could increase the effects of TMZ in glioma cells, glioma cells U87-MG were infected with lentiviral shRNA vector targeting PPM1D silencing. After PPM1D silencing was established, cells were treated with TMZ. The multiple functions of human glioma cells after PPM1D silencing and TMZ chemotherapy were detected by flow cytometry and MTT assay. Significantly differentially expressed genes were distinguished by microarray-based gene expression profiling and analyzed by gene pathway enrichment analysis and ontology assessment. Western blotting was used to establish the protein expression of the core genes. PPM1D gene silencing improves TMZ induced cell proliferation and induces cell apoptosis and cell cycle arrest. When PPM1D gene silencing combined with TMZ was performed in glioma cells, 367 genes were upregulated and 444 genes were downregulated compared with negative control. The most significant differential expression pathway was pathway in cancer and IGFR1R, PIK3R1, MAPK8 and EP300 are core genes in the network. Western blotting showed that MAPK8 and PIK3R1 protein expression levels were upregulated and RB1 protein expression was decreased. It was consistent with that detected in gene expression profiling. In conclusion, PPM1D gene silencing combined with TMZ eradicates glioma cells through cell apoptosis and cell cycle arrest. PIK3R1/AKT pathway plays a role in the multiple functions of glioma cells after PPM1D silencing and TMZ chemotherapy.
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1 

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al: European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI

2 

Chamberlain MC: Temozolomide: Therapeutic limitations in the treatment of adult high-grade gliomas. Expert Rev Neurother. 10:1537–1544. 2010. View Article : Google Scholar : PubMed/NCBI

3 

Marchesi F, Turriziani M, Tortorelli G, Avvisati G, Torino F and De Vecchis L: Triazene compounds: Mechanism of action and related DNA repair systems. Pharmacol Res. 56:275–287. 2007. View Article : Google Scholar : PubMed/NCBI

4 

Miao W, Liu X, Wang H, Fan Y, Lian S, Yang X, Wang X, Guo G, Li Q and Wang S: p53 upregulated modulator of apoptosis sensitizes drug-resistant U251 glioblastoma stem cells to temozolomide through enhanced apoptosis. Mol Med Rep. 11:4165–4173. 2015.PubMed/NCBI

5 

Martinez-Rivera M and Siddik ZH: Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53. Biochem Pharmacol. 83:1049–1062. 2012. View Article : Google Scholar : PubMed/NCBI

6 

Li S, Jiang T, Li G and Wang Z: Impact of p53 status to response of temozolomide in low MGMT expression glioblastomas: Preliminary results. Neurol Res. 30:567–570. 2008. View Article : Google Scholar : PubMed/NCBI

7 

Fiscella M, Zhang H, Fan S, Sakaguchi K, Shen S, Mercer WE, Vande Woude GF, O'Connor PM and Appella E: Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. Proc Natl Acad Sci USA. 94:6048–6053. 1997. View Article : Google Scholar : PubMed/NCBI

8 

Wang P, Rao J, Yang H, Zhao H and Yang L: Wip1 overexpression correlated with TP53/p14(ARF) pathway disruption in human astrocytomas. J Surg oncol. 104:679–684. 2011. View Article : Google Scholar : PubMed/NCBI

9 

Bulavin DV, Demidov ON, Saito S, Kauraniemi P, Phillips C, Amundson SA, Ambrosino C, Sauter G, Nebreda AR, Anderson CW, et al: Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nat Genet. 31:210–215. 2002. View Article : Google Scholar : PubMed/NCBI

10 

Li J, Yang Y, Peng Y, Austin RJ, van Eyndhoven WG, Nguyen KC, Gabriele T, McCurrach ME, Marks JR, Hoey T, et al: Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. Nat Genet. 31:133–134. 2002. View Article : Google Scholar : PubMed/NCBI

11 

Saito-Ohara F, Imoto I, Inoue J, Hosoi H, Nakagawara A, Sugimoto T and Inazawa J: PPM1D is a potential target for 17q gain in neuroblastoma. Cancer Res. 63:1876–1883. 2003.PubMed/NCBI

12 

Liang C, Guo E, Lu S, Wang S, Kang C, Chang L, Liu L, Zhang G, Wu Z, Zhao Z, et al: Over-expression of wild-type p53-induced phosphatase 1 confers poor prognosis of patients with gliomas. Brain Res. 1444:65–75. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Hirasawa A, Saito-Ohara F, Inoue J, Aoki D, Susumu N, Yokoyama T, Nozawa S, Inazawa J and Imoto I: Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets. Clin Cancer Res. 9:1995–2004. 2003.PubMed/NCBI

14 

Wang P, Rao J, Yang H, Zhao H and Yang L: PPM1D silencing by lentiviral-mediated RNA interference inhibits proliferation and invasion of human glioma cells. J Huazhong Univ Sci Technolog Med Sci. 31:94–99. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Spiro T, Liu L and Gerson S: New cytotoxic agents for the treatment of metastatic malignant melanoma: Temozolomide and related alkylating agents in combination with guanine analogues to abrogate drug resistance. Forum (Genova). 10:274–285. 2000.

16 

Shen W, Hu JA and Zheng JS: Mechanism of temozolomideinduced antitumour effects on glioma cells. J Int Med Res. 42:164–172. 2014. View Article : Google Scholar

17 

Hirose Y, Berger MS and Pieper RO: p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells. Cancer Res. 61:1957–1963. 2001.PubMed/NCBI

18 

Batista LF, Roos WP, Kaina B and Menck CF: p53 mutant human glioma cells are sensitive to UV-C-induced apoptosis due to impaired cyclobutane pyrimidine dimer removal. Mol Cancer Res. 7:237–246. 2009. View Article : Google Scholar : PubMed/NCBI

19 

Tivnan A, Zakaria Z, O'leary C, Kögel D, Pokorny JL, Sarkaria JN and Prehn JH: Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme. Front Neurosci. 9:2182015. View Article : Google Scholar : PubMed/NCBI

20 

Zhu YH, Zhang CW, Lu L, Demidov ON, Sun L, Yang L, Bulavin DV and Xiao ZC: Wipl regulates the generation of new neural cells in the adult olfactory bulb through p53-dependent cell cycle control. Stem Cells. 27:1433–1442. 2009. View Article : Google Scholar : PubMed/NCBI

21 

Tang YL, Liu X, Gao SY, Feng H, Jiang YP, Wang SS, Yang J, Jiang J, Ma XR, Tang YJ, et al: WIP1 stimulates migration and invasion of salivary adenoid cystic carcinoma by inducing MMP-9 and VEGF-C. Oncotarget. 6:9031–9044. 2015. View Article : Google Scholar : PubMed/NCBI

22 

Gilmartin AG, Faitg TH, Richter M, Groy A, Seefeld MA, Darcy MG, Peng X, Federowicz K, Yang J, Zhang SY, et al: Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction. Nat Chem Biol. 10:181–187. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Hirose Y, Katayama M, Mirzoeva OK, Berger MS and Pieper RO: Akt activation suppresses Chk2-mediated, methylating agent-induced G2 arrest and protects from temozolomide-induced mitotic catastrophe and cellular senescence. Cancer Res. 65:4861–4869. 2005. View Article : Google Scholar : PubMed/NCBI

24 

Molina JR, Hayashi Y, Stephens C and Georgescu MM: Invasive glioblastoma cells acquire stemness and increased Akt activation. Neoplasia. 12:453–463. 2010. View Article : Google Scholar : PubMed/NCBI

25 

Caporali S, Levati L, Starace G, Ragone G, Bonmassar E, Alvino E and D'Atri S: AKT is activated in an ataxia-telangiectasia and Rad3-related-dependent manner in response to temozolomide and confers protection against drug-induced cell growth inhibition. Mol Pharmacol. 74:173–183. 2008. View Article : Google Scholar : PubMed/NCBI

26 

De Salvo M, Maresca G, D'agnano I, Marchese R, Stigliano A, Gagliassi R, Brunetti E, Raza GH, De Paula U and Bucci B: Temozolomide induced c-Myc-mediated apoptosis via Akt signalling in MGMT expressing glioblastoma cells. Int J Radiat Biol. 87:518–533. 2011. View Article : Google Scholar : PubMed/NCBI

27 

Signore M, Pelacchi F, di Martino S, Runci D, Biffoni M, Giannetti S, Morgante L, De Majo M, Petricoin EF, Stancato L, et al: Combined PDK1 and CHK1 inhibition is required to kill glioblastoma stem-like cells in vitro and in vivo. Cell Death Dis. 5:e12232014. View Article : Google Scholar : PubMed/NCBI

28 

Tang Y, Liu L, Sheng M, Xiong K, Huang L, Gao Q, Wei J, Wu T, Yang S, Liu H, et al: Wip1 knockout inhibits the proliferation and enhances the migration of bone marrow mesenchymal stem cells. Exp Cell Res. 334:310–322. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Gao N, Zhang Z, Jiang BH and Shi X: Role of PI3K/AKT/mTOR signaling in the cell cycle progression of human prostate cancer. Biochem Biophys Res Commun. 310:1124–1132. 2003. View Article : Google Scholar : PubMed/NCBI

30 

Bao JM, He MY, Liu YW, Lu YJ, Hong YQ, Luo HH, Ren ZL, Zhao SC and Jiang Y: AGE/RAGE/Akt pathway contributes to prostate cancer cell proliferation by promoting Rb phosphorylation and degradation. Am J Cancer Res. 5:1741–1750. 2015.PubMed/NCBI

31 

Westhoff MA, Faham N, Marx D, Nonnenmacher L, Jennewein C, Enzenmüller S, Gonzalez P, Fulda S and Debatin KM: Sequential dosing in chemosensitization: Targeting the PI3K/Akt/mTOR pathway in neuroblastoma. PLoS one. 8:e831282013. View Article : Google Scholar

32 

Fu Y, Zhang Q, Kang C, Zhang K, Zhang J, Pu P, Wang G and Wang T: Inhibitory effects of adenovirus mediated COX-2, Akt1 and PIK3R1 shRNA on the growth of malignant tumor cells in vitro and in vivo. Int J oncol. 35:583–591. 2009.PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Wang P, Ye J, Hou C, Zhou D and Zhan S: Combination of lentivirus-mediated silencing of PPM1D and temozolomide chemotherapy eradicates malignant glioma through cell apoptosis and cell cycle arrest. Oncol Rep 36: 2544-2552, 2016.
APA
Wang, P., Ye, J., Hou, C., Zhou, D., & Zhan, S. (2016). Combination of lentivirus-mediated silencing of PPM1D and temozolomide chemotherapy eradicates malignant glioma through cell apoptosis and cell cycle arrest. Oncology Reports, 36, 2544-2552. https://doi.org/10.3892/or.2016.5089
MLA
Wang, P., Ye, J., Hou, C., Zhou, D., Zhan, S."Combination of lentivirus-mediated silencing of PPM1D and temozolomide chemotherapy eradicates malignant glioma through cell apoptosis and cell cycle arrest". Oncology Reports 36.5 (2016): 2544-2552.
Chicago
Wang, P., Ye, J., Hou, C., Zhou, D., Zhan, S."Combination of lentivirus-mediated silencing of PPM1D and temozolomide chemotherapy eradicates malignant glioma through cell apoptosis and cell cycle arrest". Oncology Reports 36, no. 5 (2016): 2544-2552. https://doi.org/10.3892/or.2016.5089
Copy and paste a formatted citation
x
Spandidos Publications style
Wang P, Ye J, Hou C, Zhou D and Zhan S: Combination of lentivirus-mediated silencing of PPM1D and temozolomide chemotherapy eradicates malignant glioma through cell apoptosis and cell cycle arrest. Oncol Rep 36: 2544-2552, 2016.
APA
Wang, P., Ye, J., Hou, C., Zhou, D., & Zhan, S. (2016). Combination of lentivirus-mediated silencing of PPM1D and temozolomide chemotherapy eradicates malignant glioma through cell apoptosis and cell cycle arrest. Oncology Reports, 36, 2544-2552. https://doi.org/10.3892/or.2016.5089
MLA
Wang, P., Ye, J., Hou, C., Zhou, D., Zhan, S."Combination of lentivirus-mediated silencing of PPM1D and temozolomide chemotherapy eradicates malignant glioma through cell apoptosis and cell cycle arrest". Oncology Reports 36.5 (2016): 2544-2552.
Chicago
Wang, P., Ye, J., Hou, C., Zhou, D., Zhan, S."Combination of lentivirus-mediated silencing of PPM1D and temozolomide chemotherapy eradicates malignant glioma through cell apoptosis and cell cycle arrest". Oncology Reports 36, no. 5 (2016): 2544-2552. https://doi.org/10.3892/or.2016.5089
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