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Farnesyltransferase Inhibitors: Current and Prospective Development for Hematologic Malignancies
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
With respect to other Ras-related proteins, studies in Caenorhabditis elegans demonstrate that FTIs can induce apoptosis by inhibiting the structurally distinct prenyltransferase enzyme Rab-GGT (GGT type II), which prenylates the Ras-related protein Rab (22). Rab proteins regulate endosomal trafficking and, like Ras, require posttranslational prenylation for membrane attachment and function. FTIs abrogate Rab-GGT activity and thereby directly induce p53-independent apoptosis. In addition, FTIs may exert cytotoxicity by inhibiting farnesylation of the Ras-related protein RHEB (Ras homologue enriched in brain). RHEB inhibition, in turn, blocks downstream mTor/S6 kinase signaling (2,3,23).
Nutritional Regulation of the Growth Plate
Published in Crystal D. Karakochuk, Kyly C. Whitfield, Tim J. Green, Klaus Kraemer, The Biology of the First 1,000 Days, 2017
One of the key immediate upstream regulators of mTORC1 is a heterodimer of tuberous sclerosis 1 and 2 (TSC1 and TSC2) (Figure 16.3). TSC1/2 acts as a GTP-ase-activating protein (GAP) for a Ras family protein called Rheb (or Ras homolog enriched in the brain). When bound to GTP, Rheb interacts with mTORC1 to stimulate its kinase activity. Like most GAPs, TSC1/2 negatively regulates the activity of Rheb (or any Ras proteins) by catalyzing the conversion of the active GTP-Rheb back to the inactive GDP-Rheb. Consequently, TSC1/2 serves as a negative regulator of mTORC1 activity. One of the many growth factors that stimulate the mTOR pathway through TSC1/2 is IGF-I. IGF-I stimulates both Ras and PI3K signaling pathways, which subsequently lead to increased phosphorylation of Erk (or extracellular signal-regulated kinases) and Akt, respectively. Because both phospho-Erk and phosphor-Akt inhibit TSC1/2, IGF-I signaling stimulates mTORC1 activity. As described in the previous section, IGF-I levels decrease during malnutrition. The decreased chondrocyte proliferation and hypertrophy during food restriction may therefore be in part mediated intracellularly through decreased IGF-I and inhibition of mTOR signaling in chondrocytes.
Roles of mTOR signaling in spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
In 1999, rapamycin received FDA approval as an immunosuppressant agent to prevent rejection in organ transplantation. Substantial evidence suggests that the dysregulation of the mTOR pathway is associated with cancer pathologies, and hyperactivation of mTORC1 is highly prevalent in human cancers. In support of this view, the mutations of genes encoding for many tumor suppressors promote mTORC1 activation.25,26 For example, P53, a well-known tumor suppressor and a major checkpoint protein, regulates mTOR activity through AMP-activated kinase (AMPK) and the tuberous sclerosis (TSC) 1/TSC2 complex.27 PTEN, a putative protein tyrosine phosphatase gene mutated in many types of human cancers, lies upstream of the mTOR complexes and negatively regulates the PI3K pathway.25,28 Additionally, mTORC2 is required for the development of tumors from human prostate epithelial cells caused by Pten deletion.29 LKB1 is a critical upstream kinase for AMPK activation and is also involved in cancer development. Mutations in the Lkb1 gene are associated with a cancer-prone disease, Peutz-Jeghers syndrome (PJS).30,31 Previous studies demonstrated LKB1 phosphorylates and activates TSC2, which further regulates the small GTPase Rheb and subsequently inhibits mTORC1.26,32 This evidence suggests that modulating of the mTOR pathway by rapamycin and its analogs (rapalogs) may have great potential to treat cancer pathogenesis. So far, there are two mTOR inhibitors approved by the U.S. Food and Drug Administration (FDA) for treating specific cancer types. Temsirolimus, the first approved rapalog, is an intravenous drug for advanced stage of renal cell carcinoma. The second approved rapalog is everolimus for treatment of renal cell cancer and also for a genetic disease caused by Tsc1/Tsc2 mutation.26
BCG-induced trained immunity in macrophage: reprograming of glucose metabolism
Published in International Reviews of Immunology, 2020
Yuntong Liu, Shu Liang, Ru Ding, Yuyang Hou, Feier Deng, Xiaohui Ma, Tiantian Song, Dongmei Yan
As a sensor of metabolic environment, mTOR coordinates metabolism and immune function in activated lymphocyte. It mediates the switch from OXPHOS to glycolysis by inducing downstream HIF-1a and c-Myc, and directly regulates the expression of enzymes in pentose phosphate pathway (PPP). mTOR have two distinct multi-protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).74 The activity of mTOR is regulated by a variety of extracellular immune and metabolic signals with complex intracellular signaling networks. The direct upstream protein of mTORC1 is Rashomolog enriched in brain (RHEB). RHEB is a small GTPase down-regulated by a GTPase activator protein called the tuberous sclerosis complex (TSC). When the complex is phosphorylated by Akt or ERK1/2, its GAP activity is inhibited, leading to RHEB and then mTORC1 activation. In trained models, it can be speculated according to known results that, PIP3, converted from phosphatidylinositol-3-kinase (PI3K), which activates Akt and ultimately leads to the activation of mTORC1.75 LPS-induced M1 macrophages display suppressed activation of AMPK and prefer glycolysis as their major glucose metabolism pathway via PI3K-AKT pathway, which is similar with the trained immunity.76
Selinexor for the treatment of multiple myeloma
Published in Expert Opinion on Pharmacotherapy, 2020
Klaus Podar, Jatin Shah, Ajai Chari, Paul G Richardson, Sundar Jagannath
Of note, preclinical synergistic or at least additive anti-MM activity has been observed with selinexor in combination with dexamethasone, PIs, melphalan, and pegylated liposomal doxorubicin (PLD). Specifically, selinexor potentiates glucocorticoid-mediated activation of the GR via enhancement of phosphorylated GR, which induces transcription of both REDD1 and BCAT2. It thereby contributes to the inhibition of the mTOR-activator Ras Homolog Enriched in Brain (RHEB), even in MM cells previously resistant to glucocorticoids. Moreover, selinexor in combination with dexamethasone upregulates Early Growth Factor Response 1 (EGFR1) protein that downregulates survivin; and the Glucocorticoid-Induced Leucine Zipper (GILZ) [61–63]. Selinexor in combination with the PIs bortezomib and carfilzomib inactivates Akt and decreases Bcl-2; activates various caspases, and their association with autophagy-inducing p62 and LC3II; and increases nuclear retention of inactivating IkBa-NFkB- complexes, even in MM cells previously resistant to PIs [59,64,65]. A synergistic effect was also observed for the combination of selinexor and melphalan, in both melphalan-sensitive as well as previously melphalan-resistant MM cell lines. Mechanistically, this synergistic effect is, at least in part, mediated through a decrease of DNA repair proteins FANC/BRAC and NFkB, and an increase of p53 [62]. Similarly, treatment of MM cell lines resistant to doxorubicin with PLD was reversed by selinexor through prevention of the nuclear export of TOP2A, thereby inducing TOP2A-mediated DNA damage and apoptosis [62].
Targeting mitochondrial quality control for treating sarcopenia: lessons from physical exercise
Published in Expert Opinion on Therapeutic Targets, 2019
Anna Picca, Riccardo Calvani, Christiaan Leeuwenburgh, Hélio José Coelho-Junior, Roberto Bernabei, Francesco Landi, Emanuele Marzetti
The mammalian target of rapamycin (mTOR) is another major signaling pathway modulated by exercise, though the outcome is different depending on the training modality [87]. The activity of mTOR is finely tuned by two energy sensors, the insulin-RACα serine/threonine protein kinase (Akt) and AMPK [88]. Following a single bout of resistance exercise, Akt is transiently activated, resulting in Rheb-mediated activation of mTOR [89]. The latter, in turn, promotes muscle growth by suppressing autophagy and stimulating protein synthesis [87]. The signaling cascade initiated by Akt does not seem to be active during endurance training [90]. Under this training modality, mTOR activity is suppressed by AMPK which also phosphorylates FoXO3, thereby upregulating autophagy and the UPS [91–93]. These adaptations may serve to mobilize muscle protein as a source of energy. At same time, stimulation of mitochondrial autophagy is necessary to clear exercise-induced organellar damage [94]. Replenishment of the mitochondrial pool is ensured by the concomitant AMPK-mediated upregulation of PGC-1α [93].