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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.
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
A novel PI3K/mTOR dual inhibitor XH002 exhibited robust antitumor activity in NSCLC
Published in Journal of Drug Targeting, 2019
Yuanhao Lv, Tingting Du, Ming Ji, Chunyang Wang, Songwen Lin, Nina Xue, Jing Jin, Heng Xu, Xiaoguang Chen
The PI3K-Akt-mTOR (PAM) pathway is one of the two important downstream branches of EGFR signalling and takes crucial roles in regulating cell survival, proliferation, metabolism and motility [6]. The PI3Ks, namely phosphoinositide 3-kinases, constitute of three classes that differ in structures and substrates specificity. After growth factors bind to receptor tyrosine kinases (RTKs), the later phosphorylate p85 regulatory subunit of class IA PI3Ks, following release of p110α catalytic subunit then phosphorylates PIP2 to PIP3. PIP3 recruits Akt and PDK1 thus facilitated Akt phosphorylation at Thr308 by PDK1. Another essential event for Akt activation is the phosphorylation at Ser473 by mTORC2. Once activated, Akt phosphorylates multiple substrates, one of them is TSC2 which inhibits Rheb in a form of TSC2/TSC1 complex, then Rheb activates mTOR kinase of mTORC1. Another substrate of Akt, PRAS40, directly binds to mTOR hereby inhibit its activity. The mTORC1 is responsible for activation of downstream effectors like p70S6K, S6RP, 4EBP1 which are crucial in ribosome translation and cell cycle. It has been proved that the alterations of PAM pathway associate with malignancy and poor prognosis of NSCLC [7]. Similarly, clinical study implied that abnormal activated p110α transduces signals to crucial kinase Akt and then promotes NSCLC progression [8]. For NSCLC, 3.1–3.9% patients were identified with PIK3CA mutation, which percent was higher in squamous cell carcinoma (8.9%) [7, 9, 10]. Interestingly, half of the PIK3CA mutation coexists with EGFR mutation and indicated poor prognosis.
Emerging role of nanomedicine in the treatment of neuropathic pain
Published in Journal of Drug Targeting, 2020
Pankaj Bidve, Namrata Prajapati, Kiran Kalia, Rakesh Tekade, Vinod Tiwari
Recent studies have suggested that glial cells (microglia, astrocytes and oligodendrocytes) play a key role in the development of NeP. In the normal physiological process, these glial cells are in non-proliferating status, but after nerve injury, these cells get activated because the release of certain mediators like ATP, glutamate and substance P thus causing mechanical allodynia (a neurological symptom of chronic pain). Some studies have suggested that mitogen-activated protein (MAP) Kinases plays an essential role in the development of NeP also some studies reported that Rheb (a Ras family member) in mTOR pathway is upregulated in astrocytes if injured spinal cord. Thus by inhibiting this pathway could have a significant potential for the treatment of NeP [28,29].