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Mtor Signaling Pathway and Mtor Inhibitors in Cancer: Progress and Challenges Zhilin Zou1,2,3†, Tao Tao4†, Hongmei Li3* and Xiao Zhu1,2*

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Mtor Signaling Pathway and Mtor Inhibitors in Cancer: Progress and Challenges Zhilin Zou1,2,3†, Tao Tao4†, Hongmei Li3* and Xiao Zhu1,2* Zou et al. Cell Biosci (2020) 10:31 https://doi.org/10.1186/s13578-020-00396-1 Cell & Bioscience REVIEW Open Access mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges Zhilin Zou1,2,3†, Tao Tao4†, Hongmei Li3* and Xiao Zhu1,2* Abstract Mammalian target of rapamycin (mTOR) regulates cell proliferation, autophagy, and apoptosis by participating in multiple signaling pathways in the body. Studies have shown that the mTOR signaling pathway is also associated with cancer, arthritis, insulin resistance, osteoporosis, and other diseases. The mTOR signaling pathway, which is often acti- vated in tumors, not only regulates gene transcription and protein synthesis to regulate cell proliferation and immune cell diferentiation but also plays an important role in tumor metabolism. Therefore, the mTOR signaling pathway is a hot target in anti-tumor therapy research. In recent years, a variety of newly discovered mTOR inhibitors have entered clinical studies, and a variety of drugs have been proven to have high activity in combination with mTOR inhibitors. The purpose of this review is to introduce the role of mTOR signaling pathway on apoptosis, autophagy, growth, and metabolism of tumor cells, and to introduce the research progress of mTOR inhibitors in the tumor feld. Keywords: mTOR signaling pathway, mTOR inhibitor, Tumor metabolism, Autophagy, Apoptosis Background tuberous sclerosis complex subunit 1 (TSC1)/tuber- Te mTOR forms two structurally and functionally dis- ous sclerosis complex subunit 2 (TSC2)/Rheb, LKBL/ tinct complexes called the mammalian target of rapa- adenosine 5′-monophosphate-activated protein kinase mycin complex 1 (mTORC1) and mammalian target (AMPK), VAM6/Rag GTPases and so on [2]. It infuences of rapamycin complex 2 (mTORC2). mTORC1 is com- transcription and protein synthesis by integrating vari- prised of mTOR, raptor, GβL and deptor, while mTORC2 ous signal stimulation, and fnally regulates apoptosis, is composed of mTOR, Rictor, GβL, PRR5, deptor, and growth, and autophagy of cells [3]. Scientists have also SIN1. mTORC1 integrates signals from multiple growth linked mTOR to various disease processes, such as tumor factors, nutrients, and energy supply to promote cell formation, arthritis, insulin resistance and osteoporo- growth when energy is sufcient and catabolism when sis [4, 5]. Among them, mTOR plays a key role in tumor the body is hungry. mTORC1 mainly regulates cell tumorigenesis and development. And multiple studies growth and metabolism, while mTORC2 mainly controls have suggested that tumors typically over-activate the cell proliferation and survival [1]. Studies have shown AKT/mTOR signaling pathway [6, 7]. Terefore, mTOR that mTOR is involved in many signaling pathways in the inhibitors are widely used in the research of targeted body, including phosphoinositide-3-kinase (PI3K)/AKT, therapy for tumors, organ transplantation, rheumatoid arthritis, and other diseases. Te purpose of this review is to elucidate the relationship between mTOR signaling *Correspondence: [email protected]; [email protected] pathway and tumor development and to introduce the † Zhilin Zou and Tao Tao contributed equally to this work research progress of mTOR inhibitors. 1 Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, China 3 Department of Pathology, Guangdong Medical University, Dongguan, China Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zou et al. Cell Biosci (2020) 10:31 Page 2 of 11 The relationship between mTOR signaling pathway the ubiquitin ligase TNF Receptor Associated Factor 2 and tumors (TRAF2) has the opposite efect by increasing the level of Tumor growth and proliferation GβL ubiquitination. Similarly, Kovalski et al. [18] proved Under normal circumstances, mTOR is a major regula- that Ras mutations can bind to mTOR of mTORC2 and tor of cell growth and division. However, in tumor cells, mitogen-activated protein kinase-associated protein 1 abnormally activated mTOR sends signals that encourage (MAPKAP1) to promote the activity of mTORC2 kinase, tumor cells to grow, metastasize, and invade new healthy thus initiating downstream proliferative cell cycle tran- tissues [8]. Among them, PI3K/phosphate and fungi scription programs. homology deleted on chromosome 10 (PTEN)/AKT/ In summary, mTOR is always stimulated in tumors to TSC pathway is the main activator of mTORC1, and gene maintain the growth, survival and proliferation of tumor mutations in this pathway can lead to malignant tumors cells, and plays a key role in tumor cell biology (Fig. 1). [9]. In addition, the expression of PTEN is often elimi- nated by epigenetic, genetic, and post-transcriptional modifcation to up-regulate the PI3K/Akt/mTOR path- Tumor metabolism way in most malignant tumors [10]. mTOR is activated when nutrients are sufcient, which Hou et al. [11] found that mutations in the PTEN gene promotes anabolism and energy storage and utiliza- led to abnormal activation of the PI3K/PTEN pathway tion. When nutrients are relatively scarce, the body must in hepatic cell carcinoma (HCC). Furthermore, dele- inhibit the activation of mTOR to keep cell material and tion of the PTEN gene induces the expression of B7-H1, energy stable. Tumor cells require large amounts of pro- which leads to immunosuppression and increases tumor teins, lipids, and nucleotides to respond to their needs progression and invasion [12]. In liver cancer, the PI3K/ for growth and division [19]. Terefore, abnormal activ- PTEN/Akt/mTOR pathway activated is involved in ity of the mTOR pathway often occurs in tumors, because tumor invasion and metastasis by up-regulating matrix mTOR plays a core role in regulating metabolism. metallopeptidase 9 (MMP-9) [13]. Similarly, the PI3K/ In breast cancer cells, the PI3K/AKT/mTORC1/sterol Akt/mTOR signaling pathway has been found to con- regulatory element-binding protein (SREBP) pathway is trol the proliferation and survival of colon cancer stem the main mechanism to induce new lipid synthesis and cells (CCSC). In sporadic colon cancer, CCSC may cause promote tumor proliferation [20]. Pyruvate kinase (PK) recurrence and metastasis [14]. Xie et al. [15] found that is involved in sugar metabolism while fatty acid synthase liver kinase B1 (LKB1) gene mutation or extracellular (FASN) is involved in the synthesis of fatty acid (FA). Tao growth signal could activate mTORC1. MTORC1 inhib- et al. [21] found that down-regulating the expression of its the activity of ring fnger protein 168 (RNF168) pro- pyruvate kinase M2 (PKM2) deactivates the AKT/mTOR tein and promotes its degradation by phosphorylating signaling pathway, thereby reducing the expression of the 60th serine of RNF168. Tis will signifcantly reduce SREBP-1c. Te reduced expression level of SREBP-1c the ubiquitination modifcation of histone H2A and inhibits the generation of FA by inhibiting the transcrip- H2A histone family member X (H2AX) after DNA dam- tion of the FASN gene, resulting in the inhibited growth age, which will inhibit the response to DNA damage and of tumor cells. In addition, Di Malta et al. [22] reported reduce the stability of the genome, leading to the pro- that the up-regulated transcription factor enhancer motion of malignant cell transformation and cancer. In (TFE) gene can activate the Rag GTPase/mTORC1 path- addition, existing research shows that Rheb is a GTPase way. In normal cells, this pathway is activated so that cells that binds and activates mTORC1 when GTP is loaded. can better absorb nutrients to maintain physiological Deng et al. [16] reported that the ubiquitination of Rheb functions. In tumor cells, this pathway is often over-acti- was regulated by growth factor signals. Ubiquitinated vated to meet the nutritional needs of the rapidly grow- Rheb inhibits Rheb activity by promoting Rheb binding ing tumor cells. However, Guri et al. [23] explored that to TSC2, leading to the inhibition of mTORC1 expres- mTORC2 promoted the production of sphingomyelin sion. In addition to the mTORC1 pathway, the mTORC2 and cardiolipin in HCC. On the one hand, sphingomyelin pathway is also involved in the regulation of the occur- and cardiac phospholipids are both structural compo- rence and development of tumor cells. Wang et al. [17] nents of cell bioflms. On the other hand, the metabolism demonstrated that OTU deubiquitinase 7B (OTUD7B) and transport of cardiac phospholipids contribute to the reduced ubiquitination level of GβL to prevent GβL from proper functioning of mitochondria, so they must be interacting with SIN1, leading to activation of mTORC2/ supplied in large quantities in rapidly proliferating tumor AKT signaling pathway and down-regulation of cells [24]. Tese results suggest that the mTORC2 sign- mTORC1 expression. Tis partially activates AKT onco- aling pathway promotes HCC proliferation and energy- genic signaling and promotes tumorigenesis. However, related lipid production. Zou et al. Cell Biosci (2020) 10:31 Page 3 of 11 Fig. 1 The relationship between mTOR and tumors.
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