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mTOR complex 2 regulates proper turnover of insulin receptor substrate-1 via the ubiquitin ligase subunit Fbw8.

The mammalian target of rapamycin (mTOR) integrates signals from nutrients and insulin via two distinct complexes, mTORC1 and mTORC2. Disruption of mTORC2 impairs the insulin-induced activation of Akt, an mTORC2 substrate. Here, we found that mTORC2 can also regulate insulin signaling at the level of insulin receptor substrate-1 (IRS-1). Despite phosphorylation at the mTORC1-mediated serine sites, which supposedly triggers IRS-1 downregulation, inactive IRS-1 accumulated in mTORC2-disrupted cells. Defective IRS-1 degradation was due to attenuated expression and phosphorylation of the ubiquitin

mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice.

Diabetic nephropathy (DN) is among the most lethal complications that occur in type 1 and type 2 diabetics. Podocyte dysfunction is postulated to be a critical event associated with proteinuria and glomerulosclerosis in glomerular diseases including DN. However, molecular mechanisms of podocyte dysfunction in the development of DN are not well understood. Here we have shown that activity of mTOR complex 1 (mTORC1), a kinase that senses nutrient availability, was enhanced in the podocytes of diabetic animals. Further, podocyte-specific mTORC1 activation induced by ablation of an upstream negati

FAK mediates the activation of cardiac fibroblasts induced by mechanical stress through regulation of the mTOR complex.

AIMS: Cardiac fibroblasts are activated by mechanical stress, but the underlying mechanisms involved remain poorly understood. In this study, we investigated whether focal adhesion kinase (FAK) plays a role in the activation of cardiac fibroblasts in response to cyclic stretch. METHODS AND RESULTS: Neonatal (NF-P3/80--third passage, 80% confluence) and adult (AF-P1/80--first passage, 80% confluence) rat cardiac fibroblasts were exposed to cyclic stretch (biaxial, 1 Hz), which enhanced FAK phosphorylation at Tyr397. Proliferation (anti-5-bromo-2'-deoxyuridine and anti-Ki67 nuclear labelling),

Shp2 negatively regulates growth in cardiomyocytes by controlling focal adhesion kinase/Src and mTOR pathways.

The aim of this study was to investigate whether Shp2 (Src homology region 2, phosphatase 2) controls focal adhesion kinase (FAK) activity and its trophic actions in cardiomyocytes. We show that low phosphorylation levels of FAK in nonstretched neonatal rat ventricular myocytes (NRVMs) coincided with a relatively high basal association of FAK with Shp2 and Shp2 phosphatase activity. Cyclic stretch (15% above initial length) enhanced FAK phosphorylation at Tyr397 and reduced FAK/Shp2 association and phosphatase activity in anti-Shp2 precipitates. Recombinant Shp2 C-terminal protein tyrosine pho

A WASp-VASP complex regulates actin polymerization at the plasma membrane.

Proteins of the Wiskott-Aldrich syndrome and Ena/VASP families both play essential functions in the regulation of actin dynamics at the cell leading edge. However, possibilities of functional interplay between members of these two families have not been addressed. Here we show that, in hemopoietic cells, recruitment of the C-terminal VCA (Verprolin homology, Cofilin homology, Acidic) domain of WASp at the plasma membrane by a ligand technique using rapamycin as an intermediate is not sufficient to elicit efficient Arp2/3 complex-mediated actin polymerization. Other domains of WASp, in particul

Attenuation of mammalian target of rapamycin activity by increased cAMP in 3T3-L1 adipocytes.

Incubating 3T3-L1 adipocytes with forskolin, which increases intracellular cAMP by activating adenylate cyclase, mimicked rapamycin by attenuating the effect of insulin on stimulating the phosphorylation of four (S/T)P sites in PHAS-I, a downstream target of the mammalian target of rapamycin (mTOR) signaling pathway. To investigate the hypothesis that increasing cAMP inhibits mTOR, the protein kinase activity of mTOR was measured in an immune complex assay with recombinant PHAS-I as substrate. Both forskolin and 8-(4-chlorophenylthio)adenosine 3'-5'-monophosphate (CPT-cAMP) prevented the activ

NFκB up-regulation of glucose transporter 3 is essential for hyperactive mammalian target of rapamycin-induced aerobic glycolysis and tumor growth.

Accumulating evidence indicates that mammalian target of rapamycin (mTOR) exerts a crucial role in aerobic glycolysis and tumorigenesis, but the underlying mechanisms remain largely obscure. Results from Tsc1- or Tsc2-null mouse embryonic fibroblasts (MEFs) and human cancer cell lines consistently indicate that the expression of glucose transporter 3 (Glut3) is dramatically up-regulated by mTOR. The rapamycin-sensitive mTOR complex 1 (mTORC1), but not the rapamycin-insensitive mTOR complex 2 (mTORC2), was involved in the regulation of Glut3 expression. Moreover, mTORC1 enhances Glut3 expressio

Tuberin activates and controls the distribution of Rac1 via association with p62 and ubiquitin through the mTORC1 signaling pathway.

Recent studies indicated that the tuberous sclerosis 2 (TSC2) gene product, tuberin, regulates Rac1 activity. However, the underlying mechanism by which tuberin regulates Rac1 activity has not been clearly elucidated to date. To better understand the molecular link between tuberin function and Rac1, we characterized the activity and distribution of Rac1 in mouse Tsc2-deficient renal tumor cells using restoration experiments with wild-type tuberin. Rac1 activity was significantly higher in tuberin-expressing cells compared with control Tsc2-deficient cells. Further, Rac1 activation was induced

Intracellular angiotensin II activates rat myometrium.

Angiotensin II is a modulator of myometrial activity; both AT(1) and AT(2) receptors are expressed in myometrium. Since in other tissues angiotensin II has been reported to activate intracellular receptors, we assessed the effects of intracellular administration of angiotensin II via microinjection on myometrium, using calcium imaging. Intracellular injection of angiotensin II increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) in myometrial cells in a dose-dependent manner. The effect was abolished by the AT(1) receptor antagonist losartan but not by the AT(2) receptor antagonist PD-123319

Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif.

Tumors that form as a result of heightened mammalian target of rapamycin (mTOR) signaling are highly vascularized. This process of angiogenesis is regulated through hypoxia-inducible factor (HIF)-mediated transcription of angiogenic factors. It is recognized that inhibition of mTOR with rapamycin can diminish the process of angiogenesis. Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb) overexpression potently enhances the activity of HIF1alpha and vascular endothelial growth factor (VEGF)-A secretion during hypoxia, which is reversed with rapamycin. Mutants of R

Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling.

Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either TSC1 or TSC2. The TSC1 and TSC2 gene products form a functional complex and inhibit phosphorylation of S6K and 4EBP1. These functions of TSC1/TSC2 are likely mediated by mTOR. Here we report that TSC2 is a GTPase-activating protein (GAP) toward Rheb, a Ras family GTPase. Rheb stimulates phosphorylation of S6K and 4EBP1. This function of Rheb is blocked by rapamycin and dominant-negative mTOR. Rheb stimulates the phosphorylation of mTOR and plays an essential role in regulation of S6K and 4EBP1 in response to nut

Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of May 2003.

As of December 31, 2003, more than 21,000 pancreas transplants had been reported to the IPTR, >15,000 in the US and >5,000 outside the US. A … he results were very similar (> or = 79% one-year GSR) in patients (approximately 10%) treated with sirolimus under various protocols. HLA-B locus matching had a significant effect on pancreas transplant outcome in the PTA category. For 1999-2003 cases the one-year rejection loss rate was 15% in recipients mismatched for 2 B-locus antigens (n=28) versus 3% …

Impact of Early Intrapatient Variability of Tacrolimus Concentrations on the Risk of Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide.

Tacrolimus (Tac) is a pivotal immunosuppressant agent used to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloHSCT). Tac is characterized by a narrow therapeutic window and a high inter-patient and intra-patient pharmacokinetic variability (IPV). Although high IPV of Tac concentrations has been associated with adverse post-transplant outcomes following solid organ transplantation, the effects of Tac IPV on alloHSCT recipients have not been determined. Tac IPV was therefore retrospectively evaluated in 128 alloHSCT recipients receiving high-dose post-tra

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… Although the optimal blood concentration of Tac has not been determined, C 0 s of 10–20 ng/mL [ 11 , 12 ] and 5–15 ng/mL [ 13 , 14 ] have been recommended as therapeutic targets when Tac is combined with methotrexate and sirolimus, respectively. … The Use of Sirolimus Combined with Tacrolimus and Low-Dose Methotrexate Is Effective in Preventing Graft-Versus-Host Disease after Unrelated Donor Hematopoietic Stem Cell Transplantation Blood 2006 108 2866 10.1182/blood.V108.11.2866.2866 15. Ganetsky A. Shah A. Miano T. Hwang W.-T. He J. …

Blockage of Autophagy for Cancer Therapy: A Comprehensive Review.

The incidence and mortality of cancer are increasing, making it a leading cause of death worldwide. Conventional treatments such as surgery, radiotherapy, and chemotherapy face significant limitations due to therapeutic resistance. Autophagy, a cellular self-degradation mechanism, plays a crucial role in cancer development, drug resistance, and treatment. This review investigates the potential of autophagy inhibition as a therapeutic strategy for cancer. A systematic search was conducted on Embase, PubMed, and Google Scholar databases from 1967 to 2024 to identify studies on autophagy inhibito

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… HCQ with Sirolimus/Vorinostat In the next phase of clinical examinations, sirolimus, vorinostat, and HCQ are investigated for their potential use in patients with advanced cancers. Sirolimus is an mTOR inhibitor approved for use in kidney transplant patients. … Experimental group 1 comprises HCQ with sirolimus, starting with a dose of HCQ (200 mg/day) and sirolimus (2 mg/day). The cycle duration is 21 days. Experimental group 2 includes HCQ with vorinostat, starting with a dose of HCQ (200 mg/day) and vorinostat (200 mg/day). …

Complex Regional Pain Syndrome in Cancer Cases: Current Knowledge and Perspectives.

BACKGROUND: Complex regional pain syndrome (CRPS) is a disabling painful disorder caused by many different and poorly understood mechanisms. It often affects the distal limbs and usually happens as consequence of a trauma. Its severity can remarkably affect patients' quality of life. When this painful complication happens in a cancer patient, the impact may be exponential. To date, there is limited knowledge of the surrounding circumstances of CRPS cases in this population. METHODS: We present two clinical cases of patients diagnosed with cancer-related pain presenting with symptoms and signs

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… The use of Everolimus has been suggested as a risk factor. 10 , 16 , 17 The reason why Everolimus can trigger CRPS remains unclear. 17 Similar cases of CRPS have been observed in patients receiving Sirolimus, another mTOR inhibitor, in renal transplant patients. 27 Several hypotheses have been proposed … Sympathetic dystrophy associated with sirolimus therapy. Transplantation . 2008;85(2):290–292. doi: 10.1097/TP.0b013e3181601230 28. Teunissen SC, Wesker W, Kruitwagen C, de Haes HC, Voest EE, de Graeff A. Symptom prevalence in patients with incurable cancer: a systematic review. …

Developments in nanotechnology approaches for the treatment of solid tumors.

Nanotechnology has revolutionized cancer therapy by introducing advanced drug delivery systems that enhance therapeutic efficacy while reducing adverse effects. By leveraging various nanoparticle platforms-including liposomes, polymeric nanoparticles, and inorganic nanoparticles-researchers have improved drug solubility, stability, and bioavailability. Additionally, new nanodevices are being engineered to respond to specific physiological conditions like temperature and pH variations, enabling controlled drug release and optimizing therapeutic outcomes. Beyond drug delivery, nanotechnology pla

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… Albumin-bound sirolimus (nab-sirolimus), an mTOR inhibitor, has been investigated across multiple malignancies. … In metastatic colorectal cancer, a phase 1/2 study assessed nab-sirolimus plus mFOLFOX and bevacizumab. …

Thrombotic microangiopathy in oncology - a review.

Thrombotic microangiopathy is a syndrome triggered by a wide spectrum of situations, some of which are specific to the Oncology setting. It is characterized by a Coombs-negative microangiopathic haemolytic anemia, thrombocytopenia and organ injury, with characteristic pathological features, resulting from platelet microvascular occlusion. TMA is rare and its cancer-related subset even more so. TMA triggered by drugs is the most common within this group, including classic chemotherapy and the latest targeted therapies. The neoplastic disease itself and hematopoietic stem-cell transplantation co

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… Another study by Shayani et al. [95] described an association between TMA and higher serum sirolimus levels, in a range believed to be nontoxic (>9,9 ng/mL). An autopsy cohort did not find correlation between CNI use and TMA [97] . … Thrombotic microangiopathy associated with sirolimus level after allogeneic hematopoietic cell transplantation with tacrolimus/sirolimus-based graft-versus-host disease prophylaxis. Biol Blood Marrow Trans. 2013;19(2):298–304. doi: 10.1016/j.bbmt.2012.10.006. 96. …

Cancer Screening in Renal Transplant Recipients: Real-World Data.

BackgroundMultiple international guidelines have endorsed cancer screening in renal transplant patients. This study aimed to describe a series of patients with post-transplant cancer and to report physicians' adherence to cancer screening guidelines.MethodsThis is a retrospective study of cancer patients who had a history of renal transplant. Charts of patients who were treated at our institution between 2012 and 2023 were reviewed, patients' clinical data were collected.ResultsThirty-nine patients were identified. The most common types of cancer were lymphoma (n = 9, 23%), squamous cell carci

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… On contrary, other agents such as mammalian target of rapamycin inhibitors (mTOR) inhibitors like sirolimus, demonstrated lower risk in comparison to CNIs [ 21 - 23 ]. … Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant. 2004;18(4):446–449. doi: 10.1111/j.1399-0012.2004.00188.x. 22. Dantal J, Hourmant M, Cantarovich D, Giral M, Blancho G, Dreno B, Soulillou JP. …

Molecular therapeutic approaches for pediatric acute myeloid leukemia.

Approximately two-thirds of children with acute myeloid leukemia (AML) are cured with intensive multi-agent chemotherapy. However, refractory and relapsed AML remains a significant source of childhood cancer mortality, highlighting the need for new therapies. Further therapy intensification with traditional cytotoxic chemotherapy in pediatric AML is not feasible given the risks of both short-term and long-term organ dysfunction. Substantial emphasis has been placed upon the development of molecularly targeted therapeutic approaches for adults and children with high-risk subtypes of AML with th

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… The mTOR inhibitor rapamycin (also known as sirolimus) and its derivatives are directly cytotoxic to primary AML samples in vitro and have proven synergistic with AML-directed cytotoxic chemotherapy in vivo in mouse models ( 88 – 90 ). … Single-cell pharmacodynamic monitoring of S6 ribosomal protein phosphorylation in AML blasts during a clinical trial combining the mTOR inhibitor sirolimus and intensive chemotherapy. Clin Cancer Res (2012) 18(6):1716–25 10.1158/1078-0432.CCR-11-2346 87. …

Long-term outcomes of children after solid organ transplantation.

Solid organ transplantation has transformed the lives of many children and adults by providing treatment for patients with organ failure who would have otherwise succumbed to their disease. The first successful transplant in 1954 was a kidney transplant between identical twins, which circumvented the problem of rejection from MHC incompatibility. Further progress in solid organ transplantation was enabled by the discovery of immunosuppressive agents such as corticosteroids and azathioprine in the 1950s and ciclosporin in 1970. Today, solid organ transplantation is a conventional treatment with

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… In patients with CNI toxicity, one option is CNI minimization or even withdrawal with intensification or substitution of alternative immunosuppressive agents, such as MMF or sirolimus. … Five-year experience using sirolimus-based, calcineurin inhibitor-free immunosuppression in pediatric renal transplantation. Pediatr Transplant. 2011;15(4):437–41. doi: 10.1111/j.1399-3046.2011.01477.x. 79. Dell-Olio D, Kelly DA. …