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Molecular Mechanisms of Brain Insulin Signaling 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Simran Chopra, Robert Hauffe, André Kleinridders
Furthermore, mTOR is a serine/threonine kinase known to exist in the form of two complexes, mTORC1 and mTORC2, although more is known about the mTORC1 signaling pathway. Upon AKT activation, mTORC1 inhibits autophagy and promotes protein synthesis in neurons (54). In addition, activated hypothalamic mTOR signaling reduces food intake (55). Furthermore, in neurons, it has been established that both insulin and IGF-1 are able to increase mRNA translation which is thought to occur via mTORC1 phosphorylation (56).
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.
BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
PAR is degraded by Poly (ADP-ribose) glycohydrolase and possibly ADP-ribose hydrolase 3, into ADP-ribose molecules, which are metabolized further to AMP. The increased AMP: ATP ratio catalyzes the metabolic sensor AMP-activated protein kinase (AMPKs). Mammalian target of rapamycin complex 1 (MTORC1) is thereby inhibited, inducing autophagy [50]. Thus, cellular energy homeostasis is regulated. In the process of making PAR, NAD+ is converted to nicotinamide. To replenish the NAD+ from nicotinamide, phosphoribosyl pyrophosphate and ATP are converted to AMP and pyrophosphate (Fig. 15.1). In the case of extreme DNA damage, as with ischemia, PARP 1 hyperactivation results in depletion of NAD+ and ATP, resulting in cell death by necrosis or apoptosis [108].
Evaluating everolimus for the treatment of breast cancer
Published in Expert Opinion on Pharmacotherapy, 2023
Camille Moreau-Bachelard, Marie Robert, Carole Gourmelon, Emmanuelle Bourbouloux, Anne Patsouris, Jean-Sébastien Frenel, Mario Campone
mTOR is a kinase, which is dysregulated in many cancers. Everolimus links to the FKBP-12 intracellular protein and forms a complex inhibiting mTORC1. The inhibition of the mTORC1 signaling pathway leads to reduced activity of ribosomal protein kinase S6 (S6K1) and eukaryotic elongation factor-binding protein 4 (4EBP–1). These two proteins are implicated in the cell cycle, angiogenesis, and glycolysis [10]. The S6K1 protein activates the functional domain of the estrogen receptor by phosphorylation. This leads to a permanent activation of the receptor. Everolimus reduces the levels of vascular endothelial growth factor (VEGF) responsible for tumoral neo-angiogenesis. Everolimus reduces glycolysis and is an inhibitor of the proliferation of tumor cells, endothelial cells, vascular smooth muscle cells, and fibroblasts. It blocks the hypoxia-inducible factor 1 (HIF-1) expression [10].
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].
Glycometabolic rearrangements–aerobic glycolysis in pancreatic ductal adenocarcinoma (PDAC): roles, regulatory networks, and therapeutic potential
Published in Expert Opinion on Therapeutic Targets, 2021
The mTOR protein exists intracellularly in two distinct complexes, mTORC1 and mTORC2, both of which are involved in regulation of cell proliferation and energy metabolism [34,148]. The mTORC1 complex, which is extensively involved in metabolism, can enhance protein translation and adipogenesis, as well as regulating glucose metabolism by converting OXPHOS of glucose to glycolysis in tumor cells. Experimental studies have shown that the activities of GLUT1 and HK2 are regulated by activated mTORC1 signaling, which directly affects cellular glucose uptake and glycolytic rate. In addition, mTORC1 promotes the upregulation of transcription factor HIF-1α, which further upregulates glycolysis-related genes including GLUT1, HK2, LDHA, and PFK [149,150]. The mTORC2 complex is involved in regulating downstream targets of the AGC kinase family and promotes glycolysis by upregulating Akt signaling, which can activate HK2 and PFK1 [151–153]. Therefore, the mTOR signaling pathway has an indispensable role in the regulation of glycolysis in tumor cells, and further exploration of its regulatory network is expected to contribute to the development of new approaches for targeted therapy with glucose metabolism.