Involvement of mTOR signaling in physiopathology and its potential therapeutic interventions

in Redox Experimental Medicine
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Irene Martín-Bocanegra Institute of Biomedicine of Seville (IBiS), Hospital University Virgen del Rocío/CSIC/University of Seville, Seville, Spain

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Thaissa Horne Institute of Biomedicine of Seville (IBiS), Hospital University Virgen del Rocío/CSIC/University of Seville, Seville, Spain

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Belén Maqueda-Hernández Institute of Biomedicine of Seville (IBiS), Hospital University Virgen del Rocío/CSIC/University of Seville, Seville, Spain

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Elena Navarro-Villarán Institute of Biomedicine of Seville (IBiS), Hospital University Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Department of Medical Physiology and Biophysics, University of Seville, Seville, Spain

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Jordi Muntané Institute of Biomedicine of Seville (IBiS), Hospital University Virgen del Rocío/CSIC/University of Seville, Seville, Spain
Department of Medical Physiology and Biophysics, University of Seville, Seville, Spain
Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Madrid, Spain

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Correspondence should be addressed to J Muntané: jmuntane-ibis@us.es
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The mammalian target of rapamycin (mTOR) is a master regulator of the cell metabolism which impacts numerous signaling involved in cell proliferation and death and recycling cell constituents to readapt to new physiological or pathological environments. mTOR is constituted by two structural and functional different complexes, mTORC1 and mTORC2. Both can be independently regulated, which has a great impact on the effectiveness of therapeutic interventions in different clinical and experimental situations. Furthermore, mTORC1 interacts with specific chaperones or immunophilins which are intracellular receptors of the immunosuppressive drugs. Low and high molecular weights of immunophilins have different intracellular functions. The present review updates the molecular structure and signaling of mTOR as well as their regulation by immunophilins and upstream and downstream signaling events, highlighting the potential therapeutic intervention of mTOR in cancer, metabolic disturbances, and aging.

Abstract

The mammalian target of rapamycin (mTOR) is a master regulator of the cell metabolism which impacts numerous signaling involved in cell proliferation and death and recycling cell constituents to readapt to new physiological or pathological environments. mTOR is constituted by two structural and functional different complexes, mTORC1 and mTORC2. Both can be independently regulated, which has a great impact on the effectiveness of therapeutic interventions in different clinical and experimental situations. Furthermore, mTORC1 interacts with specific chaperones or immunophilins which are intracellular receptors of the immunosuppressive drugs. Low and high molecular weights of immunophilins have different intracellular functions. The present review updates the molecular structure and signaling of mTOR as well as their regulation by immunophilins and upstream and downstream signaling events, highlighting the potential therapeutic intervention of mTOR in cancer, metabolic disturbances, and aging.

Introduction: Description of mTOR and FKBP

Cell growth depends on the availability of nutrients, allowing organisms to increase their size and cell number. The master regulator of nutrients on the cellular level is mammalian target of rapamycin (mTOR), which can modulate metabolism. Dysregulation of mTOR during pathological stages or excessive food intake is crucial for the development of diseases. The present review is focused on the different mechanisms involved in mTOR disturbances in pathophysiology, and the therapeutic options based on mTOR regulation impact the progression of cancer, metabolic-associated diseases, and aging (Zoncu et al. 2011).

mTOR is a serine/threonine protein kinase belonging to the phosphoinositide 3-kinase (PI3K)-related protein kinase (PIKK) family. mTOR core assembles with different proteins, leading to the generation of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) (Fig. 1). mTORC1 is characterized by the presence of a regulatory-associated protein of mTOR (RAPTOR) subunit (Hara et al. 2002), which is replaced by the rapamycin-insensitive companion of mTOR (RICTOR) in mTORC2 (Sarbassov et al. 2004). Interestingly, RAPTOR and RICTOR act as scaffolds, allowing for the binding of regulators and substrates. mTORC1 and mTORC2 contain mammalian lethal with SEC13 protein 8 (mLST8 or GβL) and DEP domain-containing mTOR-interacting protein (DEPTOR), which function as positive and negative regulators, respectively (Loewith et al. 2002, Peterson et al. 2009). Furthermore, the proline-rich AKT substrate protein of 40 kDa (PRAS40 or AKT1S1) plays an inhibitory role on mTORC1 (Zoncu et al. 2011). Other proteins such as mammalian stress-activated map kinase-interacting protein 1 (mSIN1 or MAPKAP1) and protein observed with RICTOR (PROTOR) are present in mTORC2 (Zoncu et al. 2011).

Figure 1
Figure 1

Regulation of mTOR by proliferation cell receptor and insulin growth factor receptor. mTOR is a master regulator of cellular nutritional status impacting on protein, carbohydrate, and lipid metabolism.

Citation: Redox Experimental Medicine 2024, 1; 10.1530/REM-23-0024

The content of nutrients, and in particular amino acids, regulates mTORC1 activity on ribosome biogenesis and translation, as well as downregulating autophagy (Zoncu et al. 2011) (Fig. 1). Put differently, mTORC2 responds primarily to growth factors promoting cell cycle entry, cell survival, actin cytoskeleton polarization, and anabolic output. The activation of AKT leads to the phosphorylation and inactivation of the inhibitory effect of tuberous sclerosis complex 1/2 (TSC1/2), allowing for the activation of the GTPase RHEB (Zhang et al. 2003), thus leading to the displacement of PRAS40 (Sancak et al. 2007) and RAPTOR-mediated mTORC1 recruitment to the cytoplasmic surface of lysosomes under positive regulation of amino acids (Saucedo et al. 2003) (Fig. 1). mTORC1 substrates include the eIF4E-binding protein 1 (4E-BP1) and ribosomal S6 kinase (S6K1) that control cap-dependent translation initiation and elongation, respectively (Ma & Blenis 2009). The substrates of mTORC2 include protein kinase AKT (protein kinase B), serum and glucocorticoid-inducible kinase (SGK), and the protein kinase C (PKC).

mTOR contains HEAT repeats, FAT, FK506-binding protein (FKBP)12-rapamycin-binding (FRB), kinase, and FATC domains for the binding to scaffold proteins (Yip et al. 2010). Rapamycin (or sirolimus) interacts with a peptidyl-propyl cis/trans isomerase called FK506-binding protein (FKBP12), and the resulting gain-of-function complex interacts with mTORC1 via the FRB domain, inducing conformational changes that preclude its binding to S6K1 and 4E-BP1 (Fingar & Blenis 2004). The presence of the TOR signaling (TOS) motif in the N-terminal region of RAPTOR in the mTORC1 is relevant for the specificity of the therapeutic intervention (Fingar & Blenis 2004). The rapamycin–FKBP12 complex does not interact with mTORC2 (Sarbassov et al. 2006).

Immunophilins and FKBP

Immunophilins belong to the group of highly conserved molecular chaperones with rotamase or peptidyl-propyl-(cis/trans)-isomerase (PPIase) activity. These foldases are subdivided into two subfamilies: cyclophilins when they bind the cyclic undecapeptide cyclosporine A, and the earlier mentioned FKBP when they bind to the macrolide FK506 (Kang et al. 2008). The immunosuppressive action of cyclosporin or FK506 takes place when the drug–immunophilin complex inhibits the Ser/Thr-phosphatase 2B PP2B/calcineurin activity, preventing the dephosphorylation of the transcription factor nuclear factor of activated T cells (NAFT) and its nuclear translocation, which in turn prevents the production of interleukins and interferon gamma (Li et al. 2011). Some members of the FKBP subfamily (e.g. FKBP12) also bind other macrolides such as rapamycin and derivatives. As described earlier, the rapamycin–FKBP12 complex interacts with and inhibits mTORC1. It is interesting to notice that cyclophilin and FKBP12 only show the PPIase domain (Mazaira et al. 2016), while other FKBP (FKBP38, FKBP51, FKBP52, PP5, FKBPL/WisP39, and CyP40) and steroid receptor with higher molecular weight have multiple repetitions of the tetratricopeptide repeat (TPR) domain that appears to interact with the 90 kDa heat-shock protein (HSP90) (Pratt & Toft 1997). In particular, it forms an FKBP51–Hsp90-based heterocomplex with glucocorticoid receptor (GR) in cytoplasm toward an FKBP52–Hsp90–GR complex that can be translocated to the nucleus through the dynein channel (Wochnik et al. 2005, Galigniana et al. 2010). CYP40 is usually found to be associated with estrogen receptor and progesterone receptor rather than with GR and mineralocorticoid receptor (Banerjee et al. 2008).

Other Hsp90-binding immunophilins also interact with transcription factors and protein kinase, impacting the cell cycle (Taipale et al. 2012). Put differently, FKBP51 exerts an PPIase-independent inhibitory action on NF-kB activity, while FKBP52 induces a PPIase-dependent NF-kB activation unrelated to Hsp90 (Erlejman et al. 2014). The administration of FK506 (also named tacrolimus), rapamycin (also named sirolimus), and everolimus was able to enhance the expression of FKBP12 and FKBP51 but not that of FKBP38 and FKBP52 in HepG2 cells (Navarro-Villaran et al. 2020). The pro-apoptotic properties of rapamycin and everolimus require the participation of FKBP12, while cell cycle arrest involves the participation of FKBP51 in control and treated liver cancer cells (Navarro-Villaran et al. 2020).

Regulation of mTOR-dependent cell signaling

The stimulation of tyrosine kinase receptors (TKR), as well as insulin growth factor receptor (IGFR)-dependent phosphorylation of insulin receptor substrate (IRS1), leads to the activation of the PI3K complex pathway generating phosphatidylinositol (3,4,5)-trisphosphate (PIP3) from phosphatidylinositol-4-,5-biphosphate (PIP2). PIP3 recruits another serine–threonine 3-phosphoinositide-dependent protein kinase (PDK1) that induces Thr308 phosphorylation within the N-terminal pleckstrin homology domain of AKT (Ziemba et al. 2013). The complete activation of AKT is accomplished when mTORC2 is also present colocalized with PDK1 and induces Ser473 AKT phosphorylation. The generation of PIP3 from PIP2 is reversed by PTEN. The classical pathway of AKT-dependent mTOR activation involves the phosphorylation of the inhibitor of the pathway TSC1/2 that derepress GTP-RAS homolog enriched in the brain (RHEB), which activates and induces translocation of mTORC1 to lysosomes (Fig. 1). Interestingly, S6K1 induces insulin resistance through Ser270 phosphorylation on IRS1, which exerts an inhibitory loop signaling on mTORC1 (Fig. 1) (Zhang et al. 2008, Wu et al. 2022). The activation of TKR-dependent RAS–MAPK pathway, such as ERK, also phosphorylates TSC1/2, triggering RHEB-mediated mTORC1 activation (Saxton & Sabatini 2017).

AMP-activated protein kinase (AMPK) is a sensor of the cellular ATP/AMP content. During metabolic stress, AMPK is phosphorylated and activated by liver kinase B1 (LKB1) (Shaw et al. 2004) and Ca2+/calmodulin-dependent protein kinase kinase β (aka CaMKKβ) (Nakanishi et al. 2017) (Fig. 1), as well as influenced by transforming growth factor-β-activated kinase (TAK1) (Herrero-Martin et al. 2009). Activation of AMPK leads to TSC2 phosphorylation, which stimulates its GTPase-activating protein (GAP) activity, thus preventing RHEB activation (Manning & Cantley 2003). TSC2 is also phosphorylated by glycogen synthase kinase 3 (GSK3), leading to repression of mTOR (Inoki et al. 2006). Furthermore, AMPK can also directly phosphorylate RAPTOR, which induces 14-3-3 binding to RAPTOR, resulting in allosteric inhibition of mTORC1 (Gwinn et al. 2008).

Cellular stresses result in the inhibition of mTORC1 signaling. REDD1 or (RTP801/DIG1/DDIT4) protein displaces the inhibitory 14-3-3 protein from TSC2 (DeYoung et al. 2008), and the downregulation of mTORC1 during hypoxia. The upstream molecular mechanism is based on the induction of ATM-dependent hypoxia-inducible factor 1α (HIF-1α) phosphorylation required for the transcriptional upregulation of REDD1 during hypoxia (1% oxygen) (Cam et al. 2010). The downregulation of mTOR signaling is also achieved by the disruption of the mTOR–RHEB complex with hypoxia-induced promyelocytic leukemia, as well as by p53-dependent AMPK/TSC1/2 leading mTOR inhibition during genotoxic stress (Agarwal et al. 2015).

mTORC1 strictly senses cellular amino acid content. mTORC1 activation is associated with glutamine import into cells through SLC1A5, and the leucine import to the cell in exchange for glutamine via the heterodimeric SLC7A5-SLC3A2 antiporter (Saxton & Sabatini 2017). Interestingly, lLAPTM4b induces upregulation of SLC7A5-SLC3A2 and leucine accumulation in lysosome (Cormerais et al. 2018). Furthermore, SLC38A9 in presence of intralysosomal arginine promotes interaction with the Rag-Ragulator-vATPase complex and activates mTOC1 (Fig. 1) (Wyant et al. 2017). mTORC1 activation by amino acids requires the lysosomal nutrient sensing (LYNUS) machinery, which includes the heterodimeric RAS-related GTP-binding protein (RAG) GTPases and vacuolar H+-adenosine triphosphatase ATPase (v-ATPase) complex, pentameric Ragulator, and RHEB (Settembre et al. 2013). Intralysosomal arginine and cytoplasmic leucine stimulate RAG-dependent localization of mTORC1 in the lysosome, where RHEB can activate mTORC1. Furthermore, GLS and GDH catalyze the glutaminolysis reaction to produce α-ketoglutarate, which acts as a cofactor for the activation of RAG–mTORC1 through propyl hydroxylase.

Impact of mTOR in cell metabolism

mTOR regulates ribosomes biogenesis, protein translation, nucleotide, fatty acid, and lipid synthesis while inhibiting catabolic processes such as autophagy. As earlier described, glutamine plays a relevant role during mTOR activation (Fig. 1). Furthermore, glutaminolysis is promoted by mTORC1 and mTORC2 through different mechanisms. First, mTORC1-dependent S6K1 activation increases translation of Myc which indirectly increases GLS through downregulation of miR-23a and miR-23b (Gao et al. 2009), it also prevents sirtuin 4 (SIRT4)-mediated ADP ribosylation and GDH inhibition (Csibi et al. 2013). Foxo activation results in mTOR inhibition in a glutamine synthetase (GS)-dependent manner that prevents the activation of mTOR at the cytoplasmic face of lysosomes (van der Vos et al. 2012). Overall, mTOR increases glutaminolysis, which incorporates glutamate into Krebs cycle through Myc-dependent GLS followed by GDH activity. Furthermore, Myc also increases the rate-limiting enzyme of the urea cycle ASS1 that couples citrulline and aspartate to generate argininosuccinate, leading to arginine and fumarate through ASL (Luengo et al. 2017). mTORC1 activation through eIF4E and Myc increases ODC expression that transforms ornithine into putrescine, connecting the urea cycle to the polyamine pathway (Bello-Fernandez et al. 1993). The essential branched-chain amino acids (BCAA) leucine, isoleucine, and valine can be used for the living blocks or catabolized to provide nitrogen and carbon groups. mTORC1, as well as HIF2α, Myc, and NOTCH, increases the expression of BCAA transporter SLCA5, which is catabolized by BCAT1 or BCAT2, leading to the formation of branched-chain ketoacids, which ultimately lead to acetyl-CoA and succinyl-CoA, both being incorporated into Krebs cycle or fatty acid synthesis (Mossmann et al. 2018).

mTORC1 leads to the increased expression of glucose transporters (GLUT1 or SLC2A1) and glycolytic enzymes (hexokinase 2, phosphoglucoisomerase, phosphofructokinase, enolase, and PKM2) through the transcription factors Myc and HIF1α (Buller et al. 2008, Masui et al. 2013). mTORC2, via AKT, also phosphorylates hexokinase 2 to promote its association with mitochondria (Betz et al. 2013). Glycolysis connects to the pentose phosphate pathway (PPP) at the glucose 6-phosphate level for the generation of nucleotides. Consequently, as commented earlier, PPP is also under mTOR’s control. The oxidative PPP branch uses glucose 6-phosphate to produce ribulose 5-phosphate and NADPH by the rate-limiting enzyme G6PDH. The transformation of ribulose 5-phosphate to ribose 5-phospate is catalyzed by the RPIA in the nonoxidative branch of PPP. mTORC1 stimulates the activity of G6PDH and RPIA (Evert et al. 2012). Ribose 5-phosphate is metabolized to PRPP by PRPS2 leading to downstream purine and pyrimidine nucleotide synthesis. The expression and activity of the rate-limiting enzyme PRPS2 are upregulated by mTORC1 and mTORC2 through Myc/eIF4E and AKT, respectively (Cunningham et al. 2014).

Fatty acid synthesis and fatty acid uptake are upregulated during mTOR signaling. In fact, both mTORC1 and mTORC2 induce the transcription factor SREBP1, which regulates the expression of ACLY, ACC1, FASN, and SCD1 and the fatty acid transporter CD36 (Yecies et al. 2011, Hagiwara et al. 2012, Owen et al. 2012, Ricoult et al. 2016). Furthermore, mTORC1 reduces the nuclear entry of the SREBP1 inhibitor (LIPIN1) in several cell lines (Peterson et al. 2011). Interestingly, mTORC1 stimulates phosphocholine cytidyltransferase-α (CCTα) leading to an increase in phosphatidylcholine synthesis. Furthermore, other relevant intracellular signaling and constituent lipids, such as sphingolipids, are also under mTOR regulation. Its synthetic route initiates from palmitoyl-CoA that is converted to ceramide, through sequential enzymatic reactions involving SPT. Ceramide is the precursor of sphingomyelin, sphingosine, ceramide-1-phosphate, and glucosylceramide. mTORC2 stimulates GCS involved in the metabolization of ceramide to glucosylceramide. Interestingly, S1P produced by ceramide-derived sphingosine by SPHK1 stimulates mTORC1 and mTORC2 signaling (Bouquerel et al. 2016, Guri et al. 2017).

Regulation of mTOR in physiopathology

mTOR plays a relevant role in the crossroad of cell metabolism and proliferation. Consequently, its deregulation is involved in cell homeostasis and disease. The regulation of mTOR has also been therapeutically developed in order to reduce tissue rejection in organ transplantation using immunosuppression such as cyclosporin A, FK506, or mTOR inhibitors (rapamycin and everolimus).

mTOR in cancer

mTORC1 favors tumorigenesis through phosphorylation of 4E-BP1 that derepress eIF4E-mediated translation of oncogenes such as MCL1 (Fig. 1). Moreover, as mentioned earlier, mTORC1 impacts oncogenesis through inhibition of autophagy, upregulation of HIF1α-dependent angiogenesis, and SREBP1c-dependent lipid synthesis (Fig. 2). mTORC2 stimulates tumorigenesis by activating different serine/threonine kinases such SGK and AKT both belonging to the cAMP-dependent, cGMP-dependent, and protein kinase C (AGC) kinases that promote cell proliferation and survival, glucose uptake, and cancer cell metabolism (Thomas et al. 2006, Menendez & Lupu 2007, Hsu & Sabatini 2008, Hsieh et al. 2010). The evidence that mTOR can promote cancer comes from a germline mutation associated with several familial cancer syndromes such as TSC1 and TSC2, LKB1, and PTEN that were linked to mTORC1 hyperactivity. Mutations in TSC lead to tuberous sclerosis mainly observed in benign tumors in the lung, brain, eye, kidney angiomyolipomas, and lymphangioleiomyomatosis (Sarraf et al. 2009). Peutz–Jeghers is a malignancy associated with gastrointestinal hamartomas characterized by LKB1 mutations (Zbuk & Eng 2007). PTEN mutations are observed in skin and bone outgrowths in Proteus syndrome, lipomas and hemangiomas, and intestinal polyps (Raju et al. 2002). Upstream events impacting mTOR signaling, such as inactivating NF1 mutations affecting RAS/PI3K signaling in neurofibromatosis (Ferner 2007) and activating p14 mutations stimulating RAG/mTORC1 signaling, lead to growth defects (Bohn et al. 2007). Downstream events related to regulation of mTORC1-dependent HIF1α, such as inhibitory mutation of von Hippel–Lindau, are associated with renal cell carcinoma, phaeochromocytoma, and pancreatic tumors (Siroky et al. 2009).

Figure 2
Figure 2

mTOR positively stimulates AKT, angiogenesis, cell proliferation and survival, and protein translation, as well as negatively affects autophagy.

Citation: Redox Experimental Medicine 2024, 1; 10.1530/REM-23-0024

The first generation rapalogs and derivatives (rapamycin, everolimus, and temsirolimus) were approved for the management of graft rejection in organ transplantation. Furthermore, rapamycin was approved for lymphangioleiomyomatosis; everolimus for the management of advanced stages of neuroendocrine tumors, breast cancer, nonfunctional gastrointestinal and lung neuroendocrine tumors; and temsirolimus for advanced renal carcinoma (Alzahrani 2019). The administration of rapamycin has encountered undesired side effect based on the inhibitory loop of S6K1 on ISR-dependent signaling (Fig. 1) (O'Reilly et al. 2006), MEK–ERK signaling cascade (Carracedo et al. 2008), as well as PDGFR expression (Zhang et al. 2007). In fact, the expression of S473 phosphorylated AKT in liver metastasis and skin lesions from patients with colon and breast cancer increased 4 weeks after receiving RAD001 (Everolimus, Novartis Pharma) (10 mg/day or 50 mg/week) (O'Reilly et al. 2006). These data might suggest that rapamycin is more cytostatic rather than cytotoxic in tumors. We have shown that everolimus and tacrolimus (10 µM) induce antiproliferative properties in liver cancer cells (HepG2 and Huh7) (Navarro-Villaran et al. 2016). The pro-apoptotic properties of everolimus and rapamycin were only observed at a higher concentration (100 µM) in p53-mutated cell lines (Huh7 and Hep3B) (Navarro-Villaran et al. 2016).

Tumor microenvironment is constituted by a complex interacting network of cancer and stromal cells actively releasing metabolites, inflammatory mediators, reactive oxygen and nitrogen species, and proteases that dynamically modulate tumor behavior. The expression of ROS-generating system and nitric oxide synthase, as well as antioxidant status in cells present in the tumor microenvironment regulates tumor growth, migration, invasion, survival, angiogenesis, and metastasis in cancer (Gonzalez et al. 2018). The generation of high oxidative and nitrosative stress has been related to mutagenesis and cancer progression (Gill et al. 2016), but also the induction of cell death (Gonzalez et al. 2013). By contrast, moderate levels of intracellular reactive oxygen species (Nakamura & Takada 2021) or nitric oxide (Thomas & Wink 2017) generation are pro-oncogenic because they can increase cancer metabolism and growth signaling. The administration of FK506 resulted in dose- and time-dependent increases in the production of hydrogen peroxide by glioma cells (Jin et al. 2008). However, the major side effect of FK506 vs mTORC1 inhibitors is its nephrotoxicity (Navarro-Villaran et al. 2016), which is also associated with the induction of oxidative stress (Yu et al. 2019). The impact of oxidative and nitrosative stress during the induction of cell death and cell cycle arrest by mTORC1 inhibitors (Navarro-Villaran et al. 2020) is under investigation.

Although rapamycin acutely inhibits mTORC1-dependent S6K1 activity, other mTORC1 functions such as phosphorylation of the 4E-BP1 family are not achieved by the drug (Thoreen et al. 2009). A new class of ATP competitive mTOR inhibitors, such as Torin1, PP242, WYE354, KU63794, AZD8055, WYE-125132, INK-128, and OSI-027, with little to no activity against PI3K signaling have been developed, acting on mTORC1 and mTORC2 (Yu et al. 2009, Liu et al. 2013). The use of PI3K and mTOR inhibitors strongly suppressed both S6K1 and AKT activity in cancer preclinical studies (Fan et al. 2006, Engelman et al. 2008). In the case of tumors driven by RAS mutations, a combined-based dual mTOR-PI3K and activation of MEK inhibitors might be required. Everolimus, MLN0128, and AZD014 have been assessed in hematological cancer and solid tumors (Dey et al. 2017).

mTOR inhibitors are generally well tolerated in clinical trials with the presence of mild side effects such as headache, fatigue, erythema, or skin rash, as well as the expected hypertriglyceridemia, hypercholesterolemia, and hyperglycemia (Funakoshi et al. 2013). In fact, the combined treatment based on the administration of everolimus and tamoxifen showed a significant reduction in cancer progression and increased overall survival rate compared to tamoxifen monotherapy (Bachelot et al. 2012). Other ATP-competitive inhibitors blocking mTORC1 and mTORC2 activity have been developed. Dual mTORC1 and mTORC2 inhibitor sapanisertib combined with exemestane or fulvestrant exhibited clinical benefit in postmenopausal women sensitive to everolimus or everolimus-resistant breast cancer (Lim et al. 2021).

mTOR in metabolic disturbances

As described earlier, mTOR plays a relevant role in maintaining nutritional homeostasis. mTOR is activated during nutrient disposal increasing anabolism and energy storage. mTORC1 activates protein synthesis in skeletal muscle and lipogenesis in adipose tissue, while mTORC2 promotes glucose import, glycogen synthesis, and inhibits gluconeogenesis in the liver. Fasting is related to a reduction of amino acids, glucose, and insulin blood concentration. The situation implies a reduction of mTORC1 activity through amino acid-dependent RAG and insulin-dependent AKT downregulations. In consequence, extended fasting is associated with the suppression of translation, glycogen, and lipid synthesis, as well as upregulation of autophagy, gluconeogenesis, catabolism of lipids, proteins, and glycogen. During the pathologic situation of the metabolic syndrome caused by sustained imbalance between intake and expenditure of nutrients, the chronic hyperinsulinemia kept mTORC1 activity, and induced S6K1-dependent IRS1 inhibition. This contributes to insulin resistance, which reverses the inhibitory effect of AKT on gluconeogenesis through FOXO1-dependent stimulation of the expression of the rate-limiting enzyme of gluconeogenesis PEPCK (Puigserver et al. 2003). This situation is exacerbated by the increased GSK3β inhibition of glycogen synthase in conditions of AKT downregulation (Cross et al. 1995). The sustained amino acid uptake maintains high mTORC1 activity in obesity (Newgard et al. 2009). mTOR and AKT (Fig. 1) enhance SREBP1 that upregulates PPAR-G activity, increasing lipogenesis in hepatocytes, muscle, and white adipose tissue (Tontonoz et al. 1994, Kim et al. 1998, Zhang et al. 2009).

mTOR in aging

Aging is considered a time-dependent reduction and deterioration of biological functions of the body, which can lead to disease development. In fact, centenarians with favorable aging mechanisms show delayed onset of chronic diseases (Ismail et al. 2016). Aging has highlighted a complex network of interacting intracellular signaling pathways (Kapahi et al. 2010) such as alteration of insulin (Willcox et al. 2008), mTOR signaling (Kapahi et al. 2004), mitochondrial-derived oxidative stress (Sun et al. 2002, Dai et al. 2009), senescence (Baker et al. 2011), and chronic low pro-inflammatory stage or inflammaging (Franceschi & Campisi 2014), as well as the upregulation of epigenetic silencing factors and their cofactors such as sirtuins and NAD+ levels (Kaeberlein et al. 1999, Mouchiroud et al. 2013) and circadian behavioral pattern or rhythmic genes with a positive effect on aging (Kondratov 2007, Longo & Panda 2016). The regulation of the stress response to circumvent the accumulation of metabolic by-products, as well as reducing food intake would be effective in maintaining healthy aging (Kenyon 2010). The regulation of mTOR as a master regulator of nutritional cellular status has been shown to extend life span in yeasts (Fabrizio et al. 2001), worms (Vellai et al. 2003), flies (Kapahi et al. 2004), mice (Harrison et al. 2009), and primates (Mattison et al. 2017).

The inhibition of mTOR reduces mRNA translation and the potential risk of accumulation of misfolded protein aggregates in degenerative diseases. The sustained rapamycin treatment reduces the formation of toxin huntingtin aggregates in an experimental model of Huntington’s disease (Ravikumar et al. 2004). Furthermore, the induction of autophagy as a consequence of mTOR inhibition has been widely associated with extension of life span in different organism (Toth et al. 2008, Bjedov et al. 2010, Wu et al. 2013). An impairment of adaptive immunity has been associated with the aforementioned strategies (Goldberg et al. 2015). However, the administration of RTB101, an oral mTOR inhibitor, increased IFN-induced antiviral gene expression and decreased the incidence of respiratory tract infections in older adults (Mannick et al. 2021). More experimental and clinical studies should be carried out to identify molecular mechanisms of action, clinical endpoints, and subset of patients receiving mTOR inhibitors impacting the biology of aging and immune function in older adults.

Conclusion and future prospects

The recent discoveries in the molecular upstream and downstream events regulating mTOR have reinforced its role as a signal integrator of all cellular events, impacting nutritional homeostasis. Furthermore, different studies highlighted the beneficial impact of regulating mTOR in the induction and development of actual relevant diseases such as cancer and metabolic syndrome, as well as to exert a beneficial effect on healthy aging (Table 1).

Table 1

Detailed outcomes of the studies described in the review impacting cancer, cell metabolism, and aging. Each category has been subdivided into clinical and experimental studies.

Study type/outcome References
Cancer
 Studies in patients
   mTOR inhibitors are generally well tolerated in clinical trials with the presence of mild side effects. Funakoshi et al. (2013)
   A combination of everolimus and tamoxifen showed a significant reduction in the progression of breast cancer. Bachelot et al. (2012)
   Postmenopausal women sensitive to everolimus or everolimus-resistant breast cancer exhibited clinical benefits when treated with dual mTORC1 and mTORC2 inhibitor sapanisertib combined with exemestane or fulvestrant. Lim et al. (2021)
   Hematological cancer and solid tumors have been assessed with the use of everolimus, MLN0128, and AZD014. Dey et al. (2017)
 Experimental studies
  In vitro
   Everolimus and FK506 induce antiproliferative properties in HepG2 and Huh7. The pro-apoptotic properties of everolimus and rapamycin were only observed at the highest concentration in Huh7 and Hep3B (p53-mutated cell lines). Navarro-Villaran et al. (2016)
   The use of PI3K and mTOR inhibitors strongly suppressed both S6K1 and Akt activity in human glioma cell lines. Fan et al. (2006)
  In vivo
   PI3K and mTOR inhibitors strongly suppressed both S6K1 and Akt activity in murine lung cancer. Engelman et al. (2008)
Cell metabolism
 Studies in patients
   The sustained amino acid uptake maintains high mTORC1 activity in obesity. This is exacerbated by GSK3β inhibition of glycogen synthase. Newgard et al. (2009)
 Experimental studies
  In vitro
   Chronic hyperinsulinemia sustains mTORC1 activity, which contributes to insulin resistance through FOXO1-dependent stimulation of the expression of the rate-limiting enzyme PEPCK. Puigserver et al. (2003)
   mTOR and Akt enhance SREBP1, which upregulates PPAR-γ activity, increasing lipogenesis in hepatocytes, muscle, and white adipose tissues. Tontonoz et al. (1994), Kim et al. (1998), Zhang et al. (2009)
Aging
 Studies in patients
   The administration of the oral mTOR inhibitor (RTB101) increased IFN-induced antiviral gene expression and decreased the incidence of respiratory tract infections in older adults. Mannick et al. (2021)
 Experimental studies
  In vivo
   The increase of life span in yeasts, worms, flies, mice, and primates has been associated with the regulation of mTOR as a regulator of nutritional status. Fabrizio et al. (2001), Vellai et al. (2003), Kapahi et al. (2004), Harrison et al. (2009), Mattison et al. (2017)
   The extension of life span during mTOR inhibition in different organisms has been associated with the induction of autophagy. Toth et al. (2008), Bjedov et al. (2010), Wu et al. (2013)
   Sustained rapamycin treatment reduces the accumulation of huntingtin aggregates in an experimental model of the disease. Ravikumar et al. (2004)

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This study was funded by the Instituto de Salud Carlos III (ISCiii) (PI19/01266 and PI22/00857) and Consejería de Salud y Familias (Junta de Andalucía) (PI-0216-2020 and PIP-0215-2020). We thank the Biomedical Research Network Center for Liver and Digestive Diseases (CIBEREHD) founded by the ISCIII and co-financed by European Regional Development Fund ‘A way to achieve Europe’ ERDF for their financial support.

Author contribution statement

Conceptualization: JM; Methodology: IM-B, EN-V; Investigation: JM; Data curation: IM-B, BM-H, TH; Writing – editing: IM-B, JM; Visualization, supervision, project administration, funding: JM. All authors read and agreed to the final version of the manuscript.

References

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  • Figure 1

    Regulation of mTOR by proliferation cell receptor and insulin growth factor receptor. mTOR is a master regulator of cellular nutritional status impacting on protein, carbohydrate, and lipid metabolism.

  • Figure 2

    mTOR positively stimulates AKT, angiogenesis, cell proliferation and survival, and protein translation, as well as negatively affects autophagy.

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