Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis
Abstract
:1. Introduction
2. Molecular Mechanisms of Autophagy
2.1. Types of Autophagy
2.2. The Autophagic Pathway
3. Autophagy Regulation
3.1. AMPK/mTORC1/ULK1 Pathway
3.2. PI3K/AKT/mTOR Pathway
3.3. MEK/ERK1/2 Pathway
3.4. Transcriptional Regulators of Autophagy
3.4.1. Transcription Factor EB (TFEB)
3.4.2. Forkhead Box O (FOXO)
3.4.3. Tumor Protein p53
3.4.4. Hypoxia-Inducible Factor-1 (HIF-1)
4. Paradoxical Roles of Autophagy in GBM
4.1. GBM Is Suppressed by Autophagy
Autophagy Regulation | Result | Glioma Model | Ref |
---|---|---|---|
Beclin-1 overexpression | cell proliferation inhibition, cell cycle arrest at the G2/M; apoptosis | U343, U87MG | [89,90] |
STAT3/Bcl-2 downregulation; Beclin-1 overexpression | apoptosis | U87MG | [93] |
miR224-3p overexpression | hypoxia-induced apoptosis; reduced tumor volume | U87MG, U215, athymic nude mice | [94] |
ULK2 overexpression | autophagic cell death; cell growth and astrocyte transformation inhibition | LN299; NIH nu/nu nude mice | [95] |
BCL2 Interacting Protein 3 activation | hypoxia-induced cell death | U87MG, U373 | [96] |
Cyclin B1 downregulation/PARP and Caspase-3 upregulation | cell cycle arrest, apoptosis | U251, LN229 | [97] |
AKT/mTOR pathway inhibition | cell growth inhibition; reduced tumor volume | U87MG; A172 nu/nu nude mice | [99,100,101] |
EMT regulators downregulation/N- and R-cadherin upregulation | inhibits migration and invasion capacity | GL15, U87MG | [102] |
EGFR modulation | inhibits clonogenic and migration | IRT98G, U373MG | [98] |
H3L9 demethylation | suppresses cell proliferation | LN229, U87MG | [103] |
AKT phosphorylation | senescence; reduces tumor growth | U343 athymic nu/nu mice | [89] |
MAPK14/p38 and PRKAA/AMPK/ULK1 pathway activation | senescence | U87MG | [104] |
4.2. GBM Is Promoted by Autophagy
Autophagy Regulation | Result | Glioma Model | Ref |
---|---|---|---|
Malat1 activation | promotes cell proliferation | U87MG, U118, U251, U373, D247 | [112] |
ATG4C activation | promotes cell proliferation, prevents apoptotic cell death, resistance to treatment | U87MG | [113] |
TRIM28 activation | promotes cell proliferation | U251 | [114] |
Pentraxin 3 activation | promotes GBM progression | U87MG | [115] |
Bax protein downregulation | prevents apoptotic cell death | U87MG | [116] |
BNIP3L | aids tumor progression | - | [117] |
ATG9A activation | promotes GBM growth and proliferation | - | [118] |
ATG5 activation | promotes vasculogenic mimicry | GSC primary culture | [18] |
mTOR activation | promotes vasculogenic mimicry | U87MG | [35] |
Beclin-1, HIF-1, VEGF, and MMP2 expression | increase in migration rate, the total length of VM tubes, invasion cell number | U87MG | [119] |
TGF-1 activation | promotes EMT and tumor progression | C6 glioma cells | [120] |
TGF-2 activation | promotes GBM progression and cell invasion | U251, T98, U87MG | [121] |
TMZ induced autophagy | enhances cell migration, EMT infiltration; GBM resistance to treatment | U87MG | [122,123] |
TRPC5 activation | GBM resistance to treatment | U87MG | [124] |
Autophagy activation | GBM resistance to treatment | U87MG; U251 | [125,126,127] |
MDA-9 activation | GSC sensitivity to anoikis | - | [127] |
ATF4 activation | resistance to anoikis and metastasis tumor cells | - | [128] |
mTORC1/mTORC2 activation | self-renewal | - | [129,130] |
EGFRvIII/CD133 coexpression | promotes stemness | - | [131] |
HIFs expression | promotes self-renewal, proliferation, and survival | - | [132] |
WNT-CTNN1B signaling pathway activation | aids cancer cell proliferation and stemness | - | [133] |
5. Autophagy as a Therapeutic Target for GBM
5.1. Autophagy Inhibitors
5.1.1. 3-Methyladenine (3-MA)
5.1.2. Chloroquine (CQ)
5.1.3. Quinacrine
5.1.4. ABT-737
5.1.5. Obatoclax
5.1.6. Bortezomib
5.2. Autophagy Inducers
5.2.1. Everolimus
5.2.2. Temsirolimus (CCI-779)
5.2.3. Metformin
5.2.4. Perifosine
5.2.5. Suberoylanilide Hydroxamic Acid (SAHA)
5.2.6. Imipramine
5.3. MiRNAs
5.4. Natural Products
6. Conclusions and Future Perspective
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Pathway | Target | Physiological Function | Receptor | Ref |
---|---|---|---|---|
Aggrephagy | Misfolded protein aggregates | Removes misfolded protein aggregates | p62, NBR1, OPTN, TOLLIP | [30] |
Mitophagy | Mitochondria | Removes weakened or nonfunctioning mitochondria | p62, NDP52, OPTN, NBR1, TAX1BP1 | [31] |
Reticulophagy | Endoplasmic reticulum | Controls ER morphology, turnover, ER luminal proteostasis, and recovery from stress | p62, OPTN, NBR1, BNIP3, RETREG1/FAM134B, FAM134B, RTN3, SEC62, ATL3, CCPG1, TEX264 | [30,32,33] |
Pexophagy | Peroxisome (Ub) | Degrades peroxisomes in response to the scarcity of nutrients which generates a high level of reactive oxygen species | SQSTM1/p62, NBR1 | [28,31] |
Lysophagy | Lysosome (Ub) | Degrades damaged or ruptured lysosomal membranes to prevent inflammation and cell death due to lysosomal contents leakage | SQSTM1/p62, NDP52 TAX1BP1, TRIM16 | [34] |
Xenophagy | Bacteria (Ub), Viruses | Degrades cytoplasmic bacteria and viruses | NDP52, OPTN, SQSTM1/p62, TAX1BP1 | [27,31] |
Nucleophagy | Nucleus | Degrades nuclear components necessary for terminal differentiation of keratinocytes | ATG39 | [31] |
Ribophagy | Ribosome | Degrades ribosomes during starvation to generate nucleotides and nucleosides | NUFIP1 | [30] |
Lipophagy | Lipid droplets | Regulates lipid production in response to various cellular stressors, especially in the liver | SQSTM1/p62 | [30] |
Ferritinophagy | Ferritin | Degrades ferritin in the lysosome to supply free Fe3+ to the cell for the synthesis of metalloproteins (hemoglobin and cytochromes) | NCOA4 | [28] |
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Batara, D.C.R.; Choi, M.-C.; Shin, H.-U.; Kim, H.; Kim, S.-H. Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis. Cells 2021, 10, 1411. https://doi.org/10.3390/cells10061411
Batara DCR, Choi M-C, Shin H-U, Kim H, Kim S-H. Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis. Cells. 2021; 10(6):1411. https://doi.org/10.3390/cells10061411
Chicago/Turabian StyleBatara, Don Carlo Ramos, Moon-Chang Choi, Hyeon-Uk Shin, Hyunggee Kim, and Sung-Hak Kim. 2021. "Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis" Cells 10, no. 6: 1411. https://doi.org/10.3390/cells10061411