NQO1 drives glioblastoma cell aggressiveness through EMT induction via the PI3K/Akt/mTOR/Snail pathway

Zheng,Lan; Zheng,Lan; Yang,Shipeng; Yang,Shipeng; Xu,Ran; Xu,Ran; Yang,Yang; Yang,Yang; Quan,Jishu; Quan,Jishu; Lin,Zhenhua; Lin,Zhenhua; Quan,Chunhua; Quan,Chunhua

doi:10.3892/ijo.2023.5558

NQO1 drives glioblastoma cell aggressiveness through EMT induction via the PI3K/Akt/mTOR/Snail pathway

Authors:
- Lan Zheng
- Shipeng Yang
- Ran Xu
- Yang Yang
- Jishu Quan
- Zhenhua Lin
- Chunhua Quan
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Affiliations: Central Laboratory, Affiliated Hospital of Yanbian University, Yanji, Jilin 133002, P.R. China, Key Laboratory of Pathobiology, State Ethnic Affairs Commission, Yanbian University, Yanji, Jilin 133000, P.R. China, Department of Pathology, Yanbian University Medical College, Yanji, Jilin 133000, P.R. China
Published online on: August 8, 2023 https://doi.org/10.3892/ijo.2023.5558
Article Number: 110
Copyright: © Zheng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Glioblastoma multiforme (GBM) is the most frequent and lethal cancer derived from the central nervous system, of which the mesenchymal (MES) subtype seriously influences the survival and prognosis of patients. NAD(P)H: quinone acceptor oxidoreductase 1 (NQO1) serves an important role in the carcinogenesis and progression of various types of cancer; however, the specific mechanism underlying the regulatory effects of NQO1 on GBM is unclear. Thus, the present study aimed to explore the role and mechanism of NQO1 in GBM progression. The results of bioinformatics analysis and immunohistochemistry showed that high expression of NQO1 was significantly related to the MES phenotype of GBM and shorter survival. In addition, MTT, colony formation, immunofluorescence and western blot analyses, and lung metastasis model experiments suggested that silencing NQO1 inhibited the proliferation and metastasis of GBM cells in vitro and in vivo. Furthermore, western blotting showed that the activity of the PI3K/Akt/mTOR signaling pathway was revealed to be inhibited by downregulation of NQO1 expression, whereas it was enhanced by overexpression of NQO1. Notably, co‑immunoprecipitation and ubiquitination experiments suggested that Snail was considered an important downstream target of NQO1 in GBM cells. Snail knockdown could eliminate the promoting effect of ectopic NQO1 on the proliferation and invasion of GBM cells, and reduce its effects on the activity of PI3K/Akt/mTOR signaling pathway. These results indicated that NQO1 could promote GBM aggressiveness by activating the PI3K/Akt/mTOR signaling pathway in a Snail‑dependent manner, and NQO1 and its relevant pathways may be considered novel targets for GBM therapy.

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1	Siegel RL, Miller KD, Fuchs HE and Jemal A: Cancer statistics, 2022. CA Cancer J Clin. 72:7–33. 2022. View Article : Google Scholar : PubMed/NCBI
2	Fang R, Chen X, Zhang S, Shi H, Ye Y, Shi H, Zou Z, Li P, Guo Q, Ma L, et al: EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma. Nat Commun. 12:1772021. View Article : Google Scholar :
3	Chan DT, Hsieh SY, Kam MK, Cheung TCY, Ng SCP and Poon WS: Pattern of recurrence and factors associated with cerebrospinal fluid dissemination of glioblastoma in Chinese patients. Surg Neurol Int. 7:922016. View Article : Google Scholar : PubMed/NCBI
4	Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, et al: Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 17:98–110. 2010. View Article : Google Scholar : PubMed/NCBI
5	Wang Z, Shi Y, Ying C, Jiang Y and Hu J: Hypoxia-induced PLOD1 overexpression contributes to the malignant phenotype of glioblastoma via NF-κB signaling. Oncogene. 40:1458–1475. 2021. View Article : Google Scholar : PubMed/NCBI
6	Li Y, Wang X, Qi S, Gao L, Huang G, Ren Z, Li K, Peng Y, Yi G, Guo J, et al: Spliceosome-regulated RSRP1-dependent NF-κB activation promotes the glioblastoma mesenchymal phenotype. Neuro Oncol. 23:1693–1708. 2021. View Article : Google Scholar : PubMed/NCBI
7	Tang G, Luo L, Zhang J, Zhai D, Huang D, Yin J, Zhou Q, Zhang Q and Zheng G: lncRNA LINC01057 promotes mesenchymal differentiation by activating NF-κB signaling in glioblastoma. Cancer Lett. 498:152–164. 2021. View Article : Google Scholar
8	Amicone L, Marchetti A and Cicchini C: Exosome-associated circRNAs as key regulators of EMT in cancer. Cells. 11:17162022. View Article : Google Scholar : PubMed/NCBI
9	Liu Y, Guo G, Lu Y, Chen X, Zhu L, Zhao L, Li C, Zhang Z, Jin X, Dong J, et al: Silencing IKBKE inhibits the migration and invasion of glioblastoma by promoting Snail1 degradation. Clin Transl Oncol. 24:816–828. 2022. View Article : Google Scholar
10	Yun EJ, Kim D, Hsieh JT and Baek ST: Stanniocalcin 2 drives malignant transformation of human glioblastoma cells by targeting SNAI2 and matrix Metalloproteinases. Cell Death Discov. 8:3082022. View Article : Google Scholar : PubMed/NCBI
11	Zhong C, Li X, Tao B, Peng L, Peng T, Yang X, Xia X and Chen L: LIM and SH3 protein 1 induces glioma growth and invasion through PI3K/AKT signaling and epithelial-mesenchymal transition. Biomed Pharmacother. 116:1090132019. View Article : Google Scholar
12	Nan Y, Guo L, Lu Y, Guo G, Hong R, Zhao L, Wang L, Ren B, Yu K, Zhong Y and Huang Q: miR-451 suppresses EMT and metastasis in glioma cells. Cell Cycle. 20:1270–1278. 2021. View Article : Google Scholar : PubMed/NCBI
13	Ernster L and Lindberg O: Animal mitochondria. Annu Rev Physiol. 20:13–42. 1958. View Article : Google Scholar
14	Yadav U, Kumar P and Rai V: NQO1 gene C609T polymorphism (dbSNP: rs1800566) and digestive tract cancer risk: A meta-analysis. Nutr Cancer. 70:557–568. 2018. View Article : Google Scholar : PubMed/NCBI
15	Yang Y, Zhang Y, Wu Q, Cui X, Lin Z, Liu S and Chen L: Clinical implications of high NQO1 expression in breast cancers. J Exp Clin Cancer Res. 33:142014. View Article : Google Scholar : PubMed/NCBI
16	Li Z, Zhang Y, Jin T, Men J, Lin Z, Qi P, Piao Y and Yan G: NQO1 protein expression predicts poor prognosis of non-small cell lung cancers. BMC Cancer. 15:2072015. View Article : Google Scholar : PubMed/NCBI
17	Lin L, Sun J, Tan Y, Li Z, Kong F, Shen Y, Liu C and Chen L: Prognostic implication of NQO1 overexpression in hepatocellular carcinoma. Hum Pathol. 69:31–37. 2017. View Article : Google Scholar : PubMed/NCBI
18	Madajewski B, Boatman MA, Chakrabarti G, Boothman DA and Bey EA: Depleting tumor-NQO1 potentiates anoikis and inhibits growth of NSCLC. Mol Cancer Res. 14:14–25. 2016. View Article : Google Scholar :
19	Yang Y, Zhu G, Dong B, Piao J, Chen L and Lin Z: The NQO1/PKLR axis promotes lymph node metastasis and breast cancer progression by modulating glycolytic reprogramming. Cancer Lett. 453:170–183. 2019. View Article : Google Scholar : PubMed/NCBI
20	Thapa D, Huang SB, Muñoz AR, Yang X, Bedolla RG, Hung CN, Chen CL, Huang THM, Liss MA, Reddick RL, et al: Attenuation of NAD[P]H:quinone oxidoreductase 1 aggravates prostate cancer and tumor cell plasticity through enhanced TGFβ signaling. Commun Biol. 3:122020. View Article : Google Scholar
21	Shimokawa M, Yoshizumi T, Itoh S, Iseda N, Sakata K, Yugawa K, Toshima T, Harada N, Ikegami T and Mori M: Modulation of Nqo1 activity intercepts anoikis resistance and reduces metastatic potential of hepatocellular carcinoma. Cancer Sci. 111:1228–1240. 2020. View Article : Google Scholar : PubMed/NCBI
22	Wu W, Klockow JL, Zhang M, Lafortune F, Chang E, Jin L, Wu Y and Daldrup-Link HE: Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance. Pharmacol Res. 171:1057802021. View Article : Google Scholar :
23	Liu YL, Selenica P, Zhou Q, Iasonos A, Callahan M, Feit NZ, Boland J, Vazquez-Garcia I, Mandelker D, Zehir A, et al: BRCA Mutations, homologous DNA repair deficiency, tumor mutational burden, and response to immune checkpoint inhibition in recurrent ovarian cancer. JCO Precis Oncol. 4:PO.20.000692020.PubMed/NCBI
24	Shahcheraghi SH, Tchokonte-Nana V, Lotfi M, Lotfi M, Ghorbani A and Sadeghnia HR: Wnt/beta-catenin and PI3K/Akt/mTOR signaling pathways in glioblastoma: Two main targets for drug design: A review. Curr Pharm Des. 26:1729–1741. 2020. View Article : Google Scholar : PubMed/NCBI
25	Wang X, Liu Y, Han A, Tang C, Xu R, Feng L, Yang Y, Chen L and Lin Z: The NQO1/p53/SREBP1 axis promotes hepatocellular carcinoma progression and metastasis by regulating Snail stability. Oncogene. 41:5107–5120. 2022. View Article : Google Scholar : PubMed/NCBI
26	Begleiter A and Fourie J: Induction of NQO1 in cancer cells. Methods Enzymol. 382:320–351. 2004. View Article : Google Scholar : PubMed/NCBI
27	Pradubyat N, Sakunrangsit N, Mutirangura A and Ketchart W: NADPH: Quinone oxidoreductase 1 (NQO1) mediated anti-cancer effects of plumbagin in endocrine resistant MCF7 breast cancer cells. Phytomedicine. 66:1531332020. View Article : Google Scholar
28	Yang Y, Zheng J, Wang M, Zhang J, Tian T, Wang Z, Yuan S, Liu L, Zhu P, Gu F, et al: NQO1 promotes an aggressive phenotype in hepatocellular carcinoma via amplifying ERK-NRF2 signaling. Cancer Sci. 112:641–654. 2021. View Article : Google Scholar
29	Zhou HZ, Zeng HQ, Yuan D, Ren JH, Cheng ST, Yu HB, Ren F, Wang Q, Qin YP, Huang AL and Chen J: NQO1 potentiates apoptosis evasion and upregulates XIAP via inhibiting proteasome-mediated degradation SIRT6 in hepatocellular carcinoma. Cell Commun Signal. 17:1682019. View Article : Google Scholar : PubMed/NCBI
30	Precilla SD, Biswas I, Kuduvalli SS and Anitha TS: Crosstalk between PI3K/AKT/mTOR and WNT/β-Catenin signaling in GBM-could combination therapy checkmate the collusion? Cell Signal. 95:1103502022. View Article : Google Scholar
31	Courtney KD, Corcoran RB and Engelman JA: The PI3K pathway as drug target in human cancer. J Clin Oncol. 28:1075–1083. 2010. View Article : Google Scholar :
32	Wojtas B, Gielniewski B, Wojnicki K, Maleszewska M, Mondal SS, Nauman P, Grajkowska W, Glass R, Schüller U, Herold-Mende C and Kaminska B: Gliosarcoma is driven by alterations in PI3K/Akt, RAS/MAPK pathways and characterized by collagen gene expression signature. Cancers (Basel). 11:2842019. View Article : Google Scholar : PubMed/NCBI
33	Burris HA III: Overcoming acquired resistance to anticancer therapy: Focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol. 71:829–842. 2013. View Article : Google Scholar : PubMed/NCBI
34	Ahn YJ, Lim JW and Kim H: Docosahexaenoic acid induces expression of NAD(P)H: Quinone oxidoreductase and heme oxygenase-1 through Activation of Nrf2 in cerulein-stimulated pancreatic acinar cells. Antioxidants (Basel). 9:10842020. View Article : Google Scholar : PubMed/NCBI
35	Liang S, Guo H, Ma K, Li X, Wu D, Wang Y, Wang W, Zhang S, Cui Y, Liu Y, et al: A PLCB1-PI3K-akt signaling axis activates EMT to promote cholangiocarcinoma progression. Cancer Res. 81:5889–5903. 2021. View Article : Google Scholar : PubMed/NCBI
36	Lee S, Choi EJ, Cho EJ, Lee YB, Lee JH, Yu SJ, Yoon JH and Kim YJ: Inhibition of PI3K/Akt signaling suppresses epithelial-to-mesenchymal transition in hepatocellular carcinoma through the Snail/GSK-3/beta-catenin pathway. Clin Mol Hepatol. 26:529–539. 2020. View Article : Google Scholar : PubMed/NCBI
37	Tian H, Lian R, Li Y, Liu C, Liang S, Li W, Tao T, Wu X, Ye Y, Yang X, et al: AKT-induced lncRNA VAL promotes EMT-independent metastasis through diminishing Trim16-dependent Vimentin degradation. Nat Commun. 11:51272020. View Article : Google Scholar :
38	Zhong C, Chen Y, Tao B, Peng L, Peng T, Yang X, Xia X and Chen L: LIM and SH3 protein 1 regulates cell growth and chemosensitivity of human glioblastoma via the PI3K/AKT pathway. BMC Cancer. 18:7222018. View Article : Google Scholar : PubMed/NCBI
39	Katikireddy KR, White TL, Miyajima T, Vasanth S, Raoof D, Chen Y, Price MO, Price FW and Jurkunas UV: NQO1 downregulation potentiates menadione-induced endothelial-mesenchymal transition during rosette formation in Fuchs endothelial corneal dystrophy. Free Radic Biol Med. 116:19–30. 2018. View Article : Google Scholar : PubMed/NCBI