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Alemi Serej F, Aliyari Serej H, Ebrahimi Kalan A, Mehdipour A, Aliyari Serej Z, Bravan B et al . The Role of Mammalian Target of Rapamycine Signaling Pathway in Central Nervous System Cancers: A Review. Journal of Inflammatory Diseases. 2021; 24 (5) :472-485
URL: http://journal.qums.ac.ir/article-1-2830-en.html
1- Department of Veterinary, Faculty of Veterinary Medicine, Islamic Azad University of Tabriz, Tabriz, Iran.
2- Department of Basic Science, Faculty of Veterinary Medicine, Islamic Azad University of Tabriz. Tabriz, Iran.
3- Department of Neurosciences and Cognition, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. , abbasebra@gmail.com
4- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
5- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
6- Department of Basic Sciences, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran.
7- Department of Nutrition, School of Health, Qazvin University of Medical Sciences, Qazvin, Iran.
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1. Introduction
Tumors in the Central Nervous System (CNS), especially the brain, include a wide range of different cancers, the most common of which are Glioblastoma (GBM) and Medulloblastoma (MB). A genetic disorder called Tuberous Sclerosis Complex (TSC) is another disease that predisposes patients to developing tumors [3, 4, 5]. It has been suggested that different intracellular signaling pathways are involved in the proliferation, invasion, and metastasis of CNS cancers including mTOR signaling pathway which is associated with growth, metabolism, survival, angiogenesis, autophagy, and chemotherapy resistance in these cancers [10]. Mammalian Target Of Rapamycine (mTOR) is an evolutionarily conserved serine/threonine kinase that responds to changes in cell environment including nutrient availability, energy levels, stress, and concentrations of growth factors and cytokines. The upregulated activity of the mTOR pathway leads to uncontrolled cell proliferation and, eventually, cancer development [11]. In this pathway, PI3K is responsible for the induction of mTOR activity through Akt phosphorylation and, consequently, the initiation of PI3K/Akt/mTOR signaling pathway [12]. This signaling pathway is considered as a therapeutic target in various cancers, including brain tumors, and its inhibitors are under development as effective drugs for the treatment of these cancers. The present study aims to review the role of mTOR signaling pathway and its crosstalk with other less-known molecular pathways in the development of above-mentioned cancers.

2. Materials and Methods
This is a review study. The search was conducted in Google Scholar, PubMed, Science Direct, and Scopus databases using the following keywords: Serine/threonine kinase, central nervous system neoplasms, glioblastoma, medullablastoma, and tuberous sclerosis. Finally, 78 articles were selected for review.

3. Results
PI3K/Akt/mTOR pathway is activated by Receptor Tyrosine Kinases (RTKs) such as members of ErbB receptor family, Fibroblast Growth Factor (FGF), and Insulin-Like Growth Factor-1 (IGF-1) [10]. Furthermore, some G-protein-coupled receptors (such as RAS) can activate PI3K [46]. Phosphorylated and activated Akt increases cell survival by inhibiting the proapoptotic Bcl-2 protein family such as BAD and BAX [50]. Tumor Necrosis Factor Alpha (TNFα), a cytokine whose level increases in the cancer cells, causes phosphorylation and inhibition of TSC1 protein by one of its downstream kinases called Iκb Kinase β (IKKβ). Inhibition of TSC1 prevents the conversion of the Guanosine Triphosphate (GTP)-binding form of the Rheb protein to the inactive Guanosine Diphosphate (GDP)-bound form, and thereby avoids from the inactivation of PI3K/Akt/mTOR cascade which has a substantial role in tumor angiogenesis, growth, and progression [51]. Hypoxia-induced angiogenesis, which increases the FGF and Platelet-Derived Growth Factor (PDGF) levels and, finally, causes the growth of smooth muscle and vascular endothelial cells, also exerts its effects by activating the PI3K/Akt/mTOR pathway [52]. 
Many factors contributing to the CNS malignancies are controlled by the PI3K/Akt/mTOR pathway. The effects of genetic and epigenetic factors involved in hyperactivity of the mediators of this signaling pathway on the most pediatric and adult CNS cancers including MB and GBM have been already reported [56]. Mutations in genes encoding RTKs such as Epidermal Growth Factor (EGF) receptors and the mutations leading to the inactivity of Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) gene, and a variety of mutations associated with various PI3K isoforms result in hyperactivity of PI3K/Akt/mTOR pathway [58, 59]. The role of IGF-1 receptor in development of GBM has also been studied. According to the results, glioma cells have more IGF-1 receptors than the normal brain cells which results in increased tumor growth [60].
Rapamycin and its analogues inhibit mTOR protein kinase by binding to it at a site other than the active site of the enzyme. These drugs are highly selective and are currently used as anticancer compounds in clinical practice [66]. Upon entering the cell, rapamycin binds to and inhibits the mTORC1 complex. Therefore, downstream activities of the cascade are inhibited, S6K1 and 4EBP1 proteins are not phosphorylated, and protein synthesis does not increase within the cell [67]. This controls the tumor growth through interfering with the cell cycle, proliferation, and migration. Nowadays, a new generation of mTOR inhibitors is under investigation that acts as Adenosine Triphosphate (ATP) analogues in competition with ATP to bind to the mTOR protein. Interestingly, unlike rapamycin and its analogues, this generation of mTOR inhibitors is able to inhibit both the mTORC1 and mTORC2 complexes [69].
Evidence on the role of the PI3K/Akt/mTOR pathway in GBM cell line showed that concomitant inhibition of mTOR and PI3K significantly reduces the population of cancer stem-like cells and reduces subsequent tumor growth, suggesting the ability of mTOR and PI3K inhibitors to be used as effective therapeutic agents for GBM. The increase in the activity of mTORC2 complex and rector protein in glioma cells is associated with an increase in the number of S-phase cells and in the cell motility and expression level of β1 and β2 integrins which indicate the key role of mTORC2 complex in tumor growth. In this regard and given that the increased activity of the mTORC2 complex has an important role in the development of invasive features of the tumor, this complex can be a good therapeutic target for GBM. TSC disease results from mutations in either TSC1 or TSC2 genes, leading to the inactivation of hamartin or tuberin proteins which causes dysfunction in TSC1/2 complex and hyperactivity of Rheb protein kinase in phosphorylation of S6K1 ribosomal subunit. As a result, involved cells eventually lose control of their proliferation and progress to tumor formation. It has been shown that allosteric mTOR inhibitors including rapamycin are effective in treating various TSC lesions.

4. Discussion and Conclusion
Both mTORC1 and mTORC2 complexes are two distinct sub-pathways of the PI3K/Akt/mTOR signaling pathway, which have the potential to predispose cells to tumor formation. If the malignancy is through the active mTORC1 complex, the only treatment method is to inhibit this sub-pathway with no need to inhibit the mTORC2 complex, resulting in fewer complications in patients. Therefore, inhibitors such as rapamycin and its analogues can be selectively suitable for the removal of tumors involved in this sub-pathway. However, if the malignancy is through both complexes, the use of rapamycin alone may not be sufficient to eradicate the tumor. By expanding our knowledge of the PI3K/Akt/mTOR signaling pathway and its sub-pathways and determining the exact intracellular targets of inhibitory agents in this pathway the treatment of CNS cancers can be more effective and feasible.

Ethical Considerations
Compliance with ethical guidelines

All ethical principles are considered in this article.

Funding
This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors. 

Authors' contributions
Conceptualization: Abbas Ebrahimi Kalan and Ahmad Mahdipour; Drafting: Forough Alami Serej; Research: Hossein Aliari Serej and Zeinab Aliari Serej; Edite and finalization: Balal Borazvan and Mohammad Reza Shiri shahsavar.

Conflict of interest
Authors declared no conflict of interests.

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Type of Study: Review article | Subject: Cognitive Neuroscience

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