Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2019

Open Access 01-12-2019 | Glioblastoma | Research

Knockdown ATG4C inhibits gliomas progression and promotes temozolomide chemosensitivity by suppressing autophagic flux

Authors: Zhi-peng Wen, Wen-jing Zeng, Yan-hong Chen, He Li, Jie-ya Wang, Quan Cheng, Jing Yu, Hong-hao Zhou, Zheng-zheng Liu, Jian Xiao, Xiao-ping Chen

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2019

Login to get access

Abstract

Background

Gliomas are the most common primary tumors in central nervous system. Despite advances in diagnosis and therapy, the prognosis of glioma remains gloomy. Autophagy is a cellular catabolic process that degrades proteins and damaged organelles, which is implicated in tumorigenesis and tumor progression. Autophagy related 4C cysteine peptidase (ATG4C) is an autophagy regulator responsible for cleaving of pro-LC3 and delipidation of LC3 II. This study was designed to investigate the role of ATG4C in glioma progression and temozolomide (TMZ) chemosensitivity.

Methods

The association between ATG4C mRNA expression and prognosis of gliomas patients was analyzed using the TCGA datasets. The role of ATG4C in proliferation, apoptosis, autophagy, and TMZ chemosensitivity were investigated by silencing ATG4C in vivo. Ectopic xenograft nude mice model was established to investigate the effects of ATG4C on glioma growth in vivo.

Results

The median overall survival (OS) time of patients with higher ATG4C expression was significantly reduced (HR: 1.48, p = 9.91 × 10− 7). ATG4C mRNA expression was evidently increased with the rising of glioma grade (p = 2.97 × 10− 8). Knockdown ATG4C suppressed glioma cells proliferation by inducing cell cycle arrest at G1 phase. ATG4C depletion suppressed autophagy and triggered apoptosis through ROS accumulation. Depletion of ATG4C suppressed TMZ-activated autophagy and promoted sensitivity of glioma cells to TMZ. Additionally, ATG4C knockdown suppressed the growth of glioma remarkably in nude mice.

Conclusion

ATG4C is a potential prognostic predictor for glioma patient. Targeting ATG4C may provide promising therapy strategies for gliomas treatment.
Appendix
Available only for authorised users
Literature
1.
2.
Reifenberger G, Wirsching HG, Knobbe-Thomsen CB, Weller M. Advances in the molecular genetics of gliomas - implications for classification and therapy. Nat Rev Clin Oncol. 2017;14(7):434–52.PubMedCrossRef
3.
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–20.PubMedCrossRef
4.
Zeng WJ, Yang YL, Liu ZZ, Wen ZP, Chen YH, Hu XL, Cheng Q, Xiao J, Zhao J, Chen XP. Integrative analysis of DNA methylation and gene expression identify a three-gene signature for predicting prognosis in lower-grade gliomas. Cell Physiol Biochem. 2018;47(1):428–39.PubMedCrossRef
5.
Cancer Genome Atlas Research N, Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, Cooper LA, Rheinbay E, Miller CR, Vitucci M, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372(26):2481–98.CrossRef
6.
Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro-Oncology. 2015;17(Suppl 4):iv1–iv62.PubMedPubMedCentralCrossRef
7.
Huse JT, Holland EC. Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer. 2010;10(5):319–31.PubMedCrossRef
8.
Ricard D, Idbaih A, Ducray F, Lahutte M, Hoang-Xuan K, Delattre JY. Primary brain tumours in adults. Lancet. 2012;379(9830):1984–96.PubMedCrossRef
9.
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. N Engl J Med. 2005;352(10):997–1003.PubMedCrossRef
10.
11.
Nanegrungsunk D, Onchan W, Chattipakorn N, Chattipakorn SC. Current evidence of temozolomide and bevacizumab in treatment of gliomas. Neurol Res. 2015;37(2):167–83.PubMedCrossRef
12.
Wait SD, Prabhu RS, Burri SH, Atkins TG, Asher AL. Polymeric drug delivery for the treatment of glioblastoma. Neuro-Oncology. 2015;17(Suppl 2):ii9–ii23.PubMedPubMedCentralCrossRef
13.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96.PubMedCrossRef
14.
15.
16.
17.
Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003;112(12):1809–20.PubMedPubMedCentralCrossRef
18.
Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A. 2003;100(25):15077–82.PubMedPubMedCentralCrossRef
19.
Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y, Liang C, Jung JU, Cheng JQ, Mule JJ, et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol. 2007;9(10):1142–51.PubMedPubMedCentralCrossRef
20.
21.
Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, Bause A, Li Y, Stommel JM, Dell'antonio G, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011;25(7):717–29.PubMedPubMedCentralCrossRef
22.
Huang T, Kim CK, Alvarez AA, Pangeni RP, Wan X, Song X, Shi T, Yang Y, Sastry N, Horbinski CM, et al. MST4 phosphorylation of ATG4B regulates Autophagic activity, Tumorigenicity, and Radioresistance in glioblastoma. Cancer Cell. 2017;32(6):840–55 e848.PubMedPubMedCentralCrossRef
23.
Lee SW, Kim HK, Lee NH, Yi HY, Kim HS, Hong SH, Hong YK, Joe YA. The synergistic effect of combination temozolomide and chloroquine treatment is dependent on autophagy formation and p53 status in glioma cells. Cancer Lett. 2015;360(2):195–204.PubMedCrossRef
24.
Lin CJ, Lee CC, Shih YL, Lin TY, Wang SH, Lin YF, Shih CM. Resveratrol enhances the therapeutic effect of temozolomide against malignant glioma in vitro and in vivo by inhibiting autophagy. Free Radic Biol Med. 2012;52(2):377–91.PubMedCrossRef
25.
Zanotto-Filho A, Braganhol E, Klafke K, Figueiro F, Terra SR, Paludo FJ, Morrone M, Bristot IJ, Battastini AM, Forcelini CM, et al. Autophagy inhibition improves the efficacy of curcumin/temozolomide combination therapy in glioblastomas. Cancer Lett. 2015;358(2):220–31.PubMedCrossRef
26.
27.
Rosenfeld MR, Ye X, Supko JG, Desideri S, Grossman SA, Brem S, Mikkelson T, Wang D, Chang YC, Hu J, et al. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy. 2014;10(8):1359–68.PubMedPubMedCentralCrossRef
28.
Zhang L, Li J, Ouyang L, Liu B, Cheng Y. Unraveling the roles of Atg4 proteases from autophagy modulation to targeted cancer therapy. Cancer Lett. 2016;373(1):19–26.PubMedCrossRef
29.
Li M, Hou Y, Wang J, Chen X, Shao ZM, Yin XM. Kinetics comparisons of mammalian Atg4 homologues indicate selective preferences toward diverse Atg8 substrates. J Biol Chem. 2011;286(9):7327–38.PubMedCrossRef
30.
Antonelli M, Strappazzon F, Arisi I, Brandi R, D'Onofrio M, Sambucci M, Manic G, Vitale I, Barila D, Stagni V. ATM kinase sustains breast cancer stem-like cells by promoting ATG4C expression and autophagy. Oncotarget. 2017;8(13):21692–709.PubMedPubMedCentralCrossRef
31.
Korkmaz G, le Sage C, Tekirdag KA, Agami R, Gozuacik D. miR-376b controls starvation and mTOR inhibition-related autophagy by targeting ATG4C and BECN1. Autophagy. 2012;8(2):165–76.PubMedCrossRef
32.
Korkmaz G, Tekirdag KA, Ozturk DG, Kosar A, Sezerman OU, Gozuacik D. MIR376A is a regulator of starvation-induced autophagy. PLoS One. 2013;8(12):e82556.PubMedPubMedCentralCrossRef
33.
Xu J, Fang J, Cheng Z, Fan L, Hu W, Zhou F, Shen H. Overexpression of the Kininogen-1 inhibits proliferation and induces apoptosis of glioma cells. J Exp Clin Cancer Res. 2018;37(1):180.PubMedPubMedCentralCrossRef
34.
Zhu T, Xie P, Gao YF, Huang MS, Li X, Zhang W, Zhou HH, Liu ZQ. Nucleolar and spindle-associated protein 1 is a tumor grade correlated prognosis marker for glioma patients. CNS Neurosci Ther. 2018;24(3):178–86.PubMedPubMedCentralCrossRef
35.
Huang CH, Li XJ, Zhou YZ, Luo Y, Li C, Yuan XR. Expression and clinical significance of EGFL7 in malignant glioma. J Cancer Res Clin Oncol. 2010;136(11):1737–43.PubMedCrossRef
36.
Zhang CM, Brat DJ. Genomic profiling of lower-grade gliomas uncovers cohesive disease groups: implications for diagnosis and treatment. Chin J Cancer. 2016;35:12.PubMedPubMedCentralCrossRef
37.
Zhang X, Lv QL, Huang YT, Zhang LH, Zhou HH. Akt/FoxM1 signaling pathway-mediated upregulation of MYBL2 promotes progression of human glioma. J Exp Clin Cancer Res. 2017;36(1):105.PubMedPubMedCentralCrossRef
38.
Hochegger H, Takeda S, Hunt T. Cyclin-dependent kinases and cell-cycle transitions: does one fit all? Nat Rev Mol Cell Biol. 2008;9(11):910–6.PubMedCrossRef
39.
el-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994;54(5):1169–74.PubMed
40.
41.
el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75(4):817–25.PubMedCrossRef
42.
Akin D, Wang SK, Habibzadegah-Tari P, Law B, Ostrov D, Li M, Yin XM, Kim JS, Horenstein N, Dunn WA Jr. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy. 2014;10(11):2021–35.PubMedPubMedCentralCrossRef
43.
Poillet-Perez L, Xie X, Zhan L, Yang Y, Sharp DW, Hu ZS, Su X, Maganti A, Jiang C, Lu W, et al. Autophagy maintains tumour growth through circulating arginine. Nature. 2018;563(7732):569–73.PubMedPubMedCentralCrossRef
44.
Apel A, Herr I, Schwarz H, Rodemann HP, Mayer A. Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res. 2008;68(5):1485–94.PubMedCrossRef
45.
Tran E, Chow A, Goda T, Wong A, Blakely K, Rocha M, Taeb S, Hoang VC, Liu SK, Emmenegger U. Context-dependent role of ATG4B as target for autophagy inhibition in prostate cancer therapy. Biochem Biophys Res Commun. 2013;441(4):726–31.PubMedCrossRef
46.
Andaloussi AE, Habib S, Soylemes G, Laknaur A, Elhusseini H, Al-Hendy A, Ismail N. Defective expression of ATG4D abrogates autophagy and promotes growth in human uterine fibroids. Cell Death Discov. 2017;3:17041.PubMedPubMedCentralCrossRef
47.
Fu Y, Hong L, Xu J, Zhong G, Gu Q, Gu Q, Guan Y, Zheng X, Dai Q, Luo X, et al. Discovery of a small molecule targeting autophagy via ATG4B inhibition and cell death of colorectal cancer cells in vitro and in vivo. Autophagy. 2018;20:1–17.
48.
Liu PF, Tsai KL, Hsu CJ, Tsai WL, Cheng JS, Chang HW, Shiau CW, Goan YG, Tseng HH, Wu CH, et al. Drug repurposing screening identifies Tioconazole as an ATG4 inhibitor that suppresses autophagy and sensitizes Cancer cells to chemotherapy. Theranostics. 2018;8(3):830–45.PubMedPubMedCentralCrossRef
49.
Wu Y, Ni Z, Yan X, Dai X, Hu C, Zheng Y, He F, Lian J. Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin. Autophagy. 2016;12(7):1105–17.PubMedPubMedCentralCrossRef
50.
Agrotis A, Pengo N, Burden JJ, Ketteler R. Redundancy of human ATG4 protease isoforms in autophagy and LC3/GABARAP processing revealed in cells. Autophagy. 2019;15(6):976–97.PubMedPubMedCentralCrossRef
51.
Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, Chen G, Jin S, White E. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 2007;21(11):1367–81.PubMedPubMedCentralCrossRef
52.
Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009;137(6):1062–75.PubMedPubMedCentralCrossRef
53.
Kongara S, Kravchuk O, Teplova I, Lozy F, Schulte J, Moore D, Barnard N, Neumann CA, White E, Karantza V. Autophagy regulates keratin 8 homeostasis in mammary epithelial cells and in breast tumors. Mol Cancer Res. 2010;8(6):873–84.PubMedPubMedCentralCrossRef
54.
Tal MC, Sasai M, Lee HK, Yordy B, Shadel GS, Iwasaki A. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc Natl Acad Sci U S A. 2009;106(8):2770–5.PubMedPubMedCentralCrossRef
55.
56.
Kanzawa T, Bedwell J, Kondo Y, Kondo S, Germano IM. Inhibition of DNA repair for sensitizing resistant glioma cells to temozolomide. J Neurosurg. 2003;99(6):1047–52.PubMedCrossRef
57.
Agnihotri S, Burrell K, Buczkowicz P, Remke M, Golbourn B, Chornenkyy Y, Gajadhar A, Fernandez NA, Clarke ID, Barszczyk MS, et al. ATM regulates 3-methylpurine-DNA glycosylase and promotes therapeutic resistance to alkylating agents. Cancer Discov. 2014;4(10):1198–213.PubMedPubMedCentralCrossRef
58.
Lo Dico A, Martelli C, Diceglie C, Lucignani G, Ottobrini L. Hypoxia-inducible factor-1alpha activity as a switch for glioblastoma responsiveness to Temozolomide. Front Oncol. 2018;8:249.PubMedPubMedCentralCrossRef
Metadata
Title
Knockdown ATG4C inhibits gliomas progression and promotes temozolomide chemosensitivity by suppressing autophagic flux
Authors
Zhi-peng Wen
Wen-jing Zeng
Yan-hong Chen
He Li
Jie-ya Wang
Quan Cheng
Jing Yu
Hong-hao Zhou
Zheng-zheng Liu
Jian Xiao
Xiao-ping Chen
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2019
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-019-1287-8

Other articles of this Issue 1/2019

Journal of Experimental & Clinical Cancer Research 1/2019 Go to the issue

Research

The interaction of YBX1 with G3BP1 promotes renal cell carcinoma cell metastasis via YBX1/G3BP1-SPP1- NF-κB signaling axis

Research

The arginine methyltransferase PRMT5 and PRMT1 distinctly regulate the degradation of anti-apoptotic protein CFLARL in human lung cancer cells

Research

Hypoxic exosomes facilitate angiogenesis and metastasis in esophageal squamous cell carcinoma through altering the phenotype and transcriptome of endothelial cells

Research

MicroRNA-338-3p suppresses ovarian cancer cells growth and metastasis: implication of Wnt/catenin beta and MEK/ERK signaling pathways

Research

PRDM16 functions as a suppressor of lung adenocarcinoma metastasis

Research

The regulatory ZFAS1/miR-150/ST6GAL1 crosstalk modulates sialylation of EGFR via PI3K/Akt pathway in T-cell acute lymphoblastic leukemia
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits