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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The protein mTOR (Mammalian Target of Rapamycin), also known as FRAP1 (FK506 Binding Protein 12-Rapamycin-Associated Protein 1), is encoded in humans by the FRAP1 gene. It is a serine/threonine protein kinase that regulates a number of cellular processes, including cell growth, proliferation, survival, motility, protein synthesis, and transcription. Belonging to the phosphatidylinositol 3-kinase-related kinase family, it is based at the centre of a complex regulatory network and works by sensing and integrating information from upstream pathways including energy levels, the presence of cellular nutrients (e.g., amino acids), insulin, and growth factors (such as IGF-1 and IGF-2), along with the redox status of the intracellular and extracellular environments. It transduces this information into directing the appropriate level of protein synthesis, cellular growth, and proliferation. The two best characterized molecular targets of mTORC1 signaling are p70-S6 kinase 1 (S6K1) and 4E-BP1, and the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (Figure 6.94). Details of the mTOR pathway.
mTOR Targeting Agents for the Treatment of Lymphoma and Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Andrea E. Wahner Hendrickson, Thomas E. Witzig, Scott H. Kaufmann
In addition, TORC1 enhances the translation of a different set of RNAs by phosphorylating 4E-BP1 (2,6). eIF4E is a component of a helicase complex that binds to the 7-methylguanine cap at the 5′ end of mRNAs and enhances the ability of ribosome-eIF complexes to scan the mRNA for initiation sites. 4E-BP1, in its unphosphorylated state, binds to eIF4E and inhibits the eIF4E-containing helicase complex. Activation of TORC1 signaling causes hyperphosphorylation of 4E-BP1, diminishing the stability of the 4E-BP1/eIF4E complex, and causing its dissociation. Free eIF4E then binds to the scaffold protein eIF4G and the RNA helicase eIF4A, forming an active helicase that facilitates translation of mRNAs containing long, highly folded 5′ untranslated regions. Included in this class of transcripts are messages encoding cyclin D1, c-Myc, hypoxia inducible factor-lα (HIF-lα), vascular endothelial growth factor and fibroblast growth factor as well as ribosomal proteins themselves (2,3,6). These molecules are not only critical for cell survival and proliferation, but also have the potential to be used to monitor therapy. Because HIF-lα regulates the glycolytic pathway and fluorodeoxyglucose positron emission tomography (FDG-PET) detects tumors by their elevated rates of glycolysis, FDG-PET can potentially be used to assess inhibition of this pathway after treatment with mTOR inhibitors (2,3).
Protein and amino acids
Published in Jay R Hoffman, Dietary Supplementation in Sport and Exercise, 2019
The EAAs play a role in regulating MPS by enhancing the efficiency of translation (34) due to a stimulation of peptide chain initiation relative to elongation (40). Peptide-chain initiation involves dissociation of the 80S ribosome into 40S and 60S ribosomal subunits, formation of the 43S preinitiation complex with binding of initiator methionyl-tRNA to the 40S subunit, binding of mRNA to the 43S preinitiation complex and association of the 60S ribosomal subunit to form an active 80S ribosome (74). First, peptide chain initiation is controlled by the binding of initiator methionyl tRNA to the 40S ribosomal subunit to form the 43S preinitiation complex, a reaction mediated by eukaryotic initiation factor 2 (eIF2) and regulated by eIF2B. Second is the binding of mRNA to the 43S preinitiation complex, which is mediated by eIF4F (73). During translation initiation, the eIF4E·mRNA complex binds to eIF4G and eIF4A to form the active eIF4F complex (63). The binding of eIF4E to eIF4G is controlled by 4E-binding protein 1 (4E-BP1), a repressor of translation. Binding of 4E-BP1 to eIF4E limits eIF4E availability for formation of active eIF4E·eIF4G complex and is regulated by phosphorylation of 4E-BP1 (73).
Combination of mTOR inhibitor PP242 and AMPK activator metformin exerts enhanced inhibitory effects on colorectal carcinoma cells in vitro by blocking multiple kinase pathways
Published in Journal of Chemotherapy, 2023
Cuicui Sun, Xiaoyan Yang, Zhi Jin, Zuhua Gao
mTOR constitutes a major pathway for cell proliferation, survival, differentiation, and angiogenesis [17, 18]. It is a catalytic subunit composed of at least two distinct multi-protein complexes designated as mTOR complex 1 and 2 (mTORC1 and mTORC2) [19]. mTORC1 comprises mTOR, regulatory-associated protein of mTOR (Raptor), mLST8/GbL, Deptor, and proline-rich AKT substrate 40 [20]. mTORC2 consists of mTOR, rapamycin-insensitive companion of mTOR (Rictor), mLST8/GbL, Protor, Deptor, and mammalian stress-activated protein kinase interacting protein [21]. mTORC1 controls protein synthesis rate through phosphorylation and activation of its substrates, S6K1 and 4E-BP1. Once phosphorylated, S6K1 activates ribosomal protein S6, which stimulates mRNA translation with a 5′ oligopyrimidine tract. The phosphorylation of 4E-BP1 releases eIF4E, allowing its association with eIF4G to form the active eIF4F complex, a key component of the protein synthesis machinery that is particularly important for the translation of 5′ capped mRNA. Thus, mTORC1 activation promotes ribosome biogenesis, protein synthesis, and angiogenesis to support cell growth and proliferation [22]. On the other hand, mTORC2 phosphorylates AKT, serum- and glucocorticoid-regulated kinase (SGK), and protein kinase C (PKC), which regulate cell survival and cell cycle progression [23, 24].
13-Acetoxysarcocrassolide induces apoptosis in human hepatocellular carcinoma cells through mitochondrial dysfunction and suppression of the PI3K/AKT/mTOR/p70S6K signalling pathway
Published in Pharmaceutical Biology, 2022
Chang-Min Hsu, Jen-Jie Lin, Jui-Hsin Su, Chih-I Liu
Studies have shown that when over-activated, the PI3K/AkT/mTOR signalling pathway inhibits apoptosis in several malignant tumours, promotes cell survival and proliferation, and is associated with angiogenesis, tumorigenesis, invasion, and metastasis (Engelman 2009; Fruman and Rommel 2014; Wang et al. 2018). Therefore, we studied whether the induction apoptosis could be achieved by suppressing PI3K/AkT/mTOR signalling in HA22T and HepG2 cells after 13-acetoxysarcocrasside treatment. The results showed that the expression of PI3K, AKT, and mTOR in HA22T and HepG2 cells did not change significantly after 13-acetoxysarcocrassolide treatment, whereas the expression of p-PI3K, p-AKT, and p-mTOR was significantly decreased. Studies have shown that p-mTOR activates p-p70S6K, eIF4B, p-S6, and 4EBP1, which in turn affects protein translation and proliferation (Rosner et al. 2008; Boer et al. 2010). In addition, eIF4E activity is regulated by the PI3K/mTOR pathway (Joshi and Platanias 2014; Saxton and Sabatini 2017). Our results showed that the expression of p-70S6K, p-S6, p-eIF4E, and p-eIF4B was decreased in HA22T and HepG2 cells treated with 13-acetoxysarcocrassolide but that the expression of p-4EBP1 was increased (Figure 7). Based on these results, we concluded that cytotoxicity and apoptosis can be achieved by inhibiting the PI3K/AkT/mTOR/P70S6 signalling pathway in HA22T and HepG2 cells treated with 13-acetoxysarcocrassolide.
Impaired response to sleep deprivation in heterozygous Disc1 mutant mice
Published in The World Journal of Biological Psychiatry, 2022
Chih-Yu Tsao, Li-Heng Tuan, Lukas Jyuhn-Hsiarn Lee, Chih-Min Liu, Hai-Gwo Hwu, Li-Jen Lee
Impaired eIF4E activity has been linked with various neuropsychiatric illnesses (Amorim et al. 2018). The function of eIF4E is negatively regulated by eIF4E-binding protein 1 (4E-BP1). GSK-3β has been shown to phosphorylate and inactivate 4E-BP1 and subsequently increase eIF4E-mediated protein translation (Shin et al. 2014; Ito et al. 2016). In our previous study, we showed reduced GSK-3β level in Disc1 Het mice (Baskaran et al. 2020), suggesting that the phosphorylation of 4E-BP1 and eIF4E-mediated translation activity might be affected by Disc1 haploinsufficiency under stressful condition. Collectively, the current results of our Disc1 mutant model reveal a potential mechanism of DISC1-mediated translational control under environmental stressors like SD and propose a possible connection between disrupted eIF4E function and BDNF expression in DISC1-related mental disorders, including major depression, bipolar disorder, and schizophrenia. It is not clear whether Disc1-mediated translational control of BDNF as a stress response to SD is a specific or general effect, examination of other SD-sensitive genes and proteins will be helpful to resolve this issue.