Forkhead box protein O3a promotes glioma cell resistance to temozolomide by regulating matrix metallopeptidase and β‑catenin

Sun,Datong; Yang,Shenghui; Zhang,Xufeng; Li,Sai; Wang,Lin; Chen,Junmin; Qiu,Chun; Xu,Ke

doi:10.3892/ol.2021.12580

Forkhead box protein O3a promotes glioma cell resistance to temozolomide by regulating matrix metallopeptidase and β‑catenin

Authors:
- Datong Sun
- Shenghui Yang
- Xufeng Zhang
- Sai Li
- Lin Wang
- Junmin Chen
- Chun Qiu
- Ke Xu
View Affiliations

Affiliations: Department of Oncology, Hainan Provincial People's Hospital, Haikou, Hainan 571101, P.R. China, Department of Stomatology, First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China, Clinical Immunology Section, School of Tropical Medicine and Laboratory Medicine, Hainan Medical University, Haikou, Hainan 571199, P.R. China
Published online on: February 25, 2021 https://doi.org/10.3892/ol.2021.12580
Article Number: 328
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Glioblastoma multiforme (GBM) is the most common type of malignant brain tumor. GBM is currently treated with temozolomide (TMZ), although patients often exhibit resistance to this agent. Although several mechanisms underlying the resistance of GBM to TMZ have been identified, the combination of these mechanisms is not sufficient to fully account for this phenomenon. Our previous study demonstrated that knocking down the Forkhead box protein O3a (FoxO3a) gene, a member of the FoxO subfamily of transcription factors, resulted in glioma cell sensitization to TMZ, accompanied by reduced levels of nuclear β‑catenin. The aim of the present study was to specify how FoxO3a and β‑catenin are implicated in glioma cell TMZ resistance. Using the U87 and U251 parental cell lines (also designated as sensitive cell lines) and corresponding resistant cell lines (U87‑TR and U251‑TR, generated by repeated TMZ treatments), coupled with a combined knockdown/overexpression strategy, it was revealed that FoxO3a or β‑catenin overexpression in TMZ‑treated U87 and U251 cells markedly increased cellular proliferation; co‑expression of both FoxO3a and β‑catenin resulted in the highest increase. Knockdown of either FoxO3a or β‑catenin in U87‑TR and U251‑TR cells led to a significant decrease in cell viability, which was rescued by the re‑expression of FoxO3a in FoxO3a‑knockdown cells. Subsequent experiments demonstrated that, in U87‑TR and U251‑TR cells, FoxO3a knockdown significantly reduced the protein levels of matrix metallopeptidase (MMP)9, while overexpression of FoxO3a in U87 and U251 cells enhanced the nuclear accumulation of β‑catenin, concomitantly with an increase in MMP9 levels. Furthermore, MMP9 knockdown markedly reduced the levels of nuclear β‑catenin. Collectively, the findings of the present study suggest that FoxO3a may regulate the nuclear accumulation of β‑catenin by modulating MMP9 expression, thereby rendering glioblastoma cells resistant to TMZ, and may provide unique molecular insights into the mechanisms underlying the development of TMZ resistance in GBM.

View Figures

View References

1	Gautam M, Singh S, Aggarwal M, Sharma MK, Dang S and Gabrani R: Glioblastoma multiforme; drug resistance & combination therapy. Front Anti Cancer Drug Discovery Volume. 10:1112019. View Article : Google Scholar
2	Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. New Engl J Med. 352:997–1003. 2005. View Article : Google Scholar : PubMed/NCBI
3	Clarke J, Butowski N and Chang S: Recent advances in therapy for glioblastoma. Arch Neurol. 67:279–283. 2010. View Article : Google Scholar : PubMed/NCBI
4	Wang Y, Chen L, Bao Z, Li S, You G, Yan W, Shi Z, Liu Y, Yang P, Zhang W, et al: Inhibition of STAT3 reverses alkylator resistance through modulation of the AKT and β-catenin signaling pathways. Oncol Rep. 26:1173–1180. 2011.PubMed/NCBI
5	Sinnberg T, Menzel M, Ewerth D, Sauer B, Schwarz M, Schaller M, Garbe C and Schittek B: β-Catenin signaling increases during melanoma progression and promotes tumor cell survival and chemoresistance. PLoS One. 6:e234292011. View Article : Google Scholar : PubMed/NCBI
6	Mrugala MM and Chamberlain MC: Mechanisms of disease: Temozolomide and glioblastoma-look to the future. Nat Clin Pract Oncol. 5:476–486. 2008. View Article : Google Scholar : PubMed/NCBI
7	Agnihotri S, Gajadhar AS, Ternamian C, Gorlia T, Diefes KL, Mischel PS, Kelly J, McGown G, Thorncroft M, Carlson BL, et al: Alkylpurine-DNA-N-Glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients. J Clin Invest. 122:253–266. 2012. View Article : Google Scholar : PubMed/NCBI
8	Motomura K, Natsume A and Wakabayashi T: Intravenous administration of temozolomide as a useful alternative over oral treatment with temozolomide capsules in patients with gliomas. J Neuroncol. 106:209–211. 2012. View Article : Google Scholar
9	Cahill DP, Levine KK, Betensky RA, Codd PJ, Romany CA, Reavie LB, Batchelor TT, Futreal PA, Stratton MR, Curry WT, et al: Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res. 13:2038–2045. 2007. View Article : Google Scholar : PubMed/NCBI
10	Yip S, Miao J, Cahill DP, Iafrate AJ, Aldape K, Nutt CL and Louis DN: MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance. Clin Cancer Res. 15:4622–4629. 2009. View Article : Google Scholar : PubMed/NCBI
11	Avgeropoulos NG and Batchelor TT: New treatment strategies for malignant gliomas. Oncologist. 4:209–224. 1999. View Article : Google Scholar : PubMed/NCBI
12	Xu K, Zhang Z, Pei H, Wang H, Li L and Xia Q: FoxO3a induces temozolomide resistance in glioblastoma cells via the regulation of β-catenin nuclear accumulation. Oncol Rep. 37:2391–2397. 2017. View Article : Google Scholar : PubMed/NCBI
13	Peifer M, Rauskolb C, Williams M, Riggleman B and Wieschaus E: The segment polarity gene armadillo interacts with the wingless signaling pathway in both embryonic and adult pattern formation. Development. 111:1029–1043. 1991.PubMed/NCBI
14	Noordermeer J, Klingensmith J, Perrimon N and Nusse R: Dishevelled and armadillo act in the wingless signalling pathway in drosophila. Nature. 367:80–83. 1994. View Article : Google Scholar : PubMed/NCBI
15	Zhang Z, Chen H, Chen Y and Cheng X: Significance of beta-catenin and Cyclin D1 express in glioma. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 25:1010–1012. 2009.(In Chinese). PubMed/NCBI
16	Liu X, Wang L, Zhao S, Ji X, Luo Y and Ling F: β-Catenin overexpression in malignant glioma and its role in proliferation and apoptosis in glioblastma cells. Med Oncol. 28:608–614. 2011. View Article : Google Scholar : PubMed/NCBI
17	Liu C, Tu Y, Sun X, Jiang J, Jin X, Bo X, Li Z, Bian A, Wang X, Liu D, et al: Wnt/Beta-Catenin pathway in human glioma: Expression pattern and clinical/prognostic correlations. Clin Exp Med. 11:105–112. 2011. View Article : Google Scholar : PubMed/NCBI
18	Pukkila M, Virtaniemi J, Kumpulainen E, Pirinen RT, Johansson RT, Valtonen HJ, Juhola MT and Kosma VM: Nuclear beta catenin expression is related to unfavourable outcome in oropharyngeal and hypopharyngeal squamous cell carcinoma. J Clin Pathol. 54:42–47. 2001. View Article : Google Scholar : PubMed/NCBI
19	Elzagheid A, Buhmeida A, Korkeila E, Collan Y, Syrjänen K and Pyrhönen S: Nuclear beta-catenin expression as a prognostic factor in advanced colorectal carcinoma. World J Gastroenterol. 14:3866–3871. 2008. View Article : Google Scholar : PubMed/NCBI
20	Huang CL, Liu D, Ishikawa S, Nakashima T, Nakashima N, Yokomise H, Kadota K and Ueno M: Wnt1 overexpression promotes tumour progression in non-small cell lung cancer. Eur J Cancer. 44:2680–2688. 2008. View Article : Google Scholar : PubMed/NCBI
21	Noda T, Nagano H, Takemasa I, Yoshioka S, Murakami M, Wada H, Kobayashi S, Marubashi S, Takeda Y, Dono K, et al: Activation of wnt/beta-catenin signalling pathway induces chemoresistance to interferon-alpha/5-fluorouracil combination therapy for hepatocellular carcinoma. Br J Cancer. 100:1647–1658. 2009. View Article : Google Scholar : PubMed/NCBI
22	Accili D and Arden KC: FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell. 117:421–426. 2004. View Article : Google Scholar : PubMed/NCBI
23	Myatt SS and Lam EWF: The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 7:847–859. 2007. View Article : Google Scholar : PubMed/NCBI
24	Chen J, Gomes AR, Monteiro LJ, Wong SY, Wu LH, Ng TT, Karadedou CT, Millour J, Ip YC, Cheung YN, et al: Constitutively nuclear FOXO3a localization predicts poor survival and promotes akt phosphorylation in breast cancer. PLoS One. 5:e122932010. View Article : Google Scholar : PubMed/NCBI
25	Storz P, Döppler H, Copland JA, Simpson KJ and Toker A: FOXO3a promotes tumor cell invasion through the induction of matrix metalloproteinases. Mol Cell Biol. 29:4906–4917. 2009. View Article : Google Scholar : PubMed/NCBI
26	Xu K, Pei H, Zhang Z, Dong S, Fu RJ, Wang WM and Wang H: FoxO3a mediates glioma cell invasion by regulating MMP9 expression. Oncol Rep. 36:3044–3050. 2016. View Article : Google Scholar : PubMed/NCBI
27	Sun J, Wei H, Yi J, Chen J and Tian B: Human umbilical cord mesenchymal stem cells restore imatinib and doxorubicin sensitivity in drug-resistant chronic myeloid leukemia cells. Int J Clin Exp Med. 11:2142–2147. 2018.
28	Aldonza MBD, Hong JY and Lee SK: Paclitaxel-Resistant cancer cell-derived secretomes elicit ABCB1-associated docetaxel cross-resistance and escape from apoptosis through FOXO3a-driven glycolytic regulation. Exp Mol Med. 49:e2862017. View Article : Google Scholar : PubMed/NCBI
29	Dwivedi A, Slater SC and George SJ: MMP-9 and-12 cause N-cadherin shedding and thereby beta-catenin signalling and vascular smooth muscle cell proliferation. Cardiovasc Res. 81:178–186. 2009. View Article : Google Scholar : PubMed/NCBI
30	Tenbaum SP, Ordóñez-Morán P, Puig I, Chicote I, Arqués O, Landolfi S, Fernández Y, Herance JR, Gispert JD, Mendizabal L, et al: β-Catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med. 18:8922012. View Article : Google Scholar : PubMed/NCBI
31	Kahlert U, Nikkhah G and Maciaczyk J: Epithelial-To-Mesenchymal (-like) transition as a relevant molecular event in malignant gliomas. Cancer Lett. 331:131–138. 2013. View Article : Google Scholar : PubMed/NCBI
32	Laios A, Mohamed BM, Kelly L, Flavin R, Finn S, McEvoy L, Gallagher M, Martin C, Sheils O, Ring M, et al: Pre-Treatment of platinum resistant ovarian cancer cells with an MMP-9/MMP-2 inhibitor prior to cisplatin enhances cytotoxicity as determined by high content screening. Int J Mol Sci. 14:2085–2103. 2013. View Article : Google Scholar : PubMed/NCBI
33	Fiore E, Fusco C, Romero P and Stamenkovic I: Matrix metalloproteinase 9 (MMP-9/gelatinase B) proteolytically cleaves ICAM-1 and participates in tumor cell resistance to natural killer cell-mediated cytotoxicity. Oncogene. 21:5213–5223. 2002. View Article : Google Scholar : PubMed/NCBI