Autophagy—A Hidden but Important Actor on Oral Cancer Scene
Abstract
:1. Introduction
2. Oral Cancer
3. Autophagy
- (1)
- signals such as starvation activate the ULK complex, which will bind to the PtdIns3K complex following AMPK activation or mTOR suppression [35];
- (2)
- following induction, the ULK complex, PtdIns3K complex and the ATG9 complex orchestrated action will trigger the phagophore assembly at the phagophore assembly site [35];
- (3)
- ATG12 and LC3 conjugation systems are key players in regulating the phagophore elongation to the autophagosome. mTOR, the major autophagy inhibitory factor, suppresses autophagy as response to abundant nutrients conditions. This suppressive action is mediated by class I PI3K and AKT signaling [35];
- (4)
- SQSTM1/p62 (sequestosome 1) receptor protein will consequently interact with both LC3 and ubiquitin chains [35];
- (5)
- Further, the autophagosome will fuse with a lysosome, resulting the autolysosome formation. Inside autolysosome, the autophagosome constituents will be hydrolytically degraded. The trapped SQSTM1 will be degraded in the autolysosome, which highlight SQSTM1′s role as an autophagy flux marker [35].
3.1. Autophagy—An Important AKT/mTOR Pathway Target
3.2. Autophagy—Important Actor on Oral Cancers Scene
3.2.1. Oncogenes and Tumor Suppressors that Control the Autophagy Pathway
3.2.2. Autophagy Regarded as a Tumor Suppressor
Autophagic Cell Death
Autophagic Senescence
Inflammation
Oxidative Stress and Genomic Instability
3.2.3. Autophagy Regarded as a Tumor Growth Promoter
- -
- at early stages of tumor development, autophagy plays the role of a tumor suppressor by ensuring damaged proteins and organelles degradation. In this context, autophagy should be regarded as controlling system, able to decreases ROS production and, consequently, maintaining genomic stability. Autophagy also can prevent necrotic cell death in apoptosis-defective cells, ensuring in this way the decrease of local inflammation and tumor growth. In some situations autophagy can lead to apoptotic cell death.
- -
- at later stages of tumor evolution, activated autophagy plays the role of cancer cell survival and tumor growth promoter, by suppling metabolic stressed tumor cells with nutrients, in order to sustain energy generation in mitochondria and biosynthetic pathways. Unfortunately, autophagy represents one of the main actors in developing the resistance to cancer therapy. Adapted from [100].
3.2.4. Autophagy Related Chemoresistance in Oral Cancer
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Oncogene Product or Tumor Suppressor | Effect on Autophagy Pathway | Reference |
---|---|---|
(1) mTOR | Negative regulator | [74,75,76,77,78,79,80] |
(2) PTEN | Inducer | [46,81] |
(3) Beclin-1 | Inducer | [74] |
(4) DAPK | Inducer | [82] |
(5) BCL-2; BCL-XL | Negative regulator | [74] |
(6) c-FLIP | Negative regulator | [83,84] |
(7) P53 | Negative regulator/Inducer | [85,86,87,88] |
Publication Title | Proposed Molecular Mechanism for Sustaining the Tumor Suppressor Role of Autophagy | Reference |
---|---|---|
Autophagic cell death: the story of a misnomer | Autophagic cell death | [94] |
Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy | Autophagic cell death | [95] |
Anti-neoplastic activity of the cytosolic FoxO1 results from autophagic cell death | Autophagic cell death | [45] |
Autophagy mediates the mitotic senescence transition | Autophagic senescence | [96] |
The dynamic nature of autophagy in cancer | Autophagic senescence | [97] |
Cancer-related inflammation | Inflammation downregulation | [98] |
Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis | Inflammation downregulation | [99] |
The double-edged sword of autophagy modulation in cancer | Inflammation downregulation | [74] |
The Roles of Autophagy in Cancer. | Inflammation downregulation | [100] |
Autophagy in immunity and inflammation | Inflammation downregulation | [101] |
The Atg5–Atg12 conjugate associates with innate antiviral immune responses. | Inflammation downregulation | [102] |
Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production | Inflammation downregulation | [103] |
Autophagy in mammalian development and differentiation | Inflammation downregulation | [7] |
Autophagy in health and disease: A comprehensive review. | Inflammation downregulation | [104] |
Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine | Inflammation downregulation | [105] |
Reactive species: a cell damaging rout assisting to chemical carcinogens | Oxidative stress and genome instability | [106] |
Mitochondrial gateways to cancer | Oxidative stress and genome instability | [107] |
Autophagy suppresses tumor progression by limiting chromosomal instability | Oxidative stress and genome instability | [108] |
Oncosuppressive functions of autophagy | Oxidative stress and genome instability | [109] |
PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1 | Oxidative stress and genome instability | [110] |
A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62 | Oxidative stress and genome instability | [111] |
Publication Title | Proposed Molecular Mechanism | Reference |
---|---|---|
Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis | Beclin-1 dependent regulation | [99] |
The double-edged sword of autophagy modulation in cancer. | Stress tolerance increase | [74] |
The Roles of Autophagy in Cancer. | Inflammation downregulation | [100] |
Targeting GRP75 improves HSP90 inhibitor efficacy by enhancing P53-mediated apoptosis in hepatocellular carcinoma | Ras activation | [88] |
Autophagy suppresses tumor progression by limiting chromosomal instability | Ras activation | [108] |
Autophagy opposes P53-mediated tumor barrier to facilitate tumorigenesis in a model of PALB2-associated hereditary breast cancer | P53 suppression | [112] |
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Alexandra, T.; Marina, I.M.; Daniela, M.; Ioana, S.I.; Maria, B.; Radu, R.; Maria, T.A.; Tudor, S.; Maria, G. Autophagy—A Hidden but Important Actor on Oral Cancer Scene. Int. J. Mol. Sci. 2020, 21, 9325. https://doi.org/10.3390/ijms21239325
Alexandra T, Marina IM, Daniela M, Ioana SI, Maria B, Radu R, Maria TA, Tudor S, Maria G. Autophagy—A Hidden but Important Actor on Oral Cancer Scene. International Journal of Molecular Sciences. 2020; 21(23):9325. https://doi.org/10.3390/ijms21239325
Chicago/Turabian StyleAlexandra, Totan, Imre Melescanu Marina, Miricescu Daniela, Stanescu Iulia Ioana, BencZe Maria, Radulescu Radu, Tancu Ana Maria, Spinu Tudor, and Greabu Maria. 2020. "Autophagy—A Hidden but Important Actor on Oral Cancer Scene" International Journal of Molecular Sciences 21, no. 23: 9325. https://doi.org/10.3390/ijms21239325