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PubMed2005

The mammalian target of the rapamycin (mTOR) kinase pathway: its role in tumourigenesis and targeted antitumour therapy.

The mammalian target of rapamycin (mTOR) is a kinase responsible for mitogen-induced cell proliferation/survival signaling. Its activation in response to mitogens leads to a cell-cycle progression from G1 to S phase. mTOR controls the activation of ribosomal protein translation and the initiation of cap-dependent translation. A role of mTOR signaling pathway dysregulation in tumourigenesis is postulated. mTOR and pathways upstream of this kinase were found to be frequently upregulated in neoplastic diseases. Therefore, it is also an attractive target for antitumour therapy. Several mTOR inhibitors were developed, including rapamycin and its analogues: CCI-779, RAD001 and AP23573. After promising phase I studies, their potential clinical significance is currently under evaluation in several phase II-III trials on patients with solid tumours and some hematological malignancies.

Antibiotics, Antineoplastic↗
PubMed2006

Suppression of the mTOR-raptor signaling pathway by the inhibitor of heat shock protein 90 geldanamycin.

Heat shock protein 90 (Hsp90) was co-immunoprecipitated with raptor, the binding partner of the mammalian target of rapamycin (mTOR) from HEK293 cells. Hsp90 was detected in the anti-raptor antibody immunoprecipitates prepared from the cell extract by immunoblot analysis using the anti-Hsp90 antibody, and the association of these two proteins was confirmed by immunoprecipitation from the cells co-expressing Hsp90 and raptor as epitope-tagged molecules. Geldanamycin, a potent inhibitor of Hsp90, disrupted the in vivo binding of Hsp90 to raptor without affecting the association of raptor and mTOR, and suppressed the phosphorylation by mTOR of the downstream translational regulators p70 S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). The protein kinase activity of S6K as well as the phosphorylation of the substrate, 40S ribosomal protein S6, were lowered in the geldanamycin-treated cells. These results indicate that Hsp90 is involved in the regulation of protein translation by facilitating the phosphorylation reaction of 4E-BP1 and S6K catalyzed by the mTOR/raptor complex through the association with raptor, and that the mTOR signaling pathway is a novel target of geldanamycin.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation.

Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Amino acid signaling through the mammalian target of rapamycin (mTOR) pathway: Role of glutamine and of cell shrinkage.

Mammalian target of rapamycin (mTOR) mediates a signaling pathway that couples amino acid availability to S6 kinase (S6K) activation, translational initiation and cell growth rate, participating to a versatile checkpoint that inspects the energy status of the cell. The pathway is activated by branched-chain amino acids (BCAA), leucine being the most effective, whereas amino acid dearth and ATP shortage lead to its deactivation. Glutamine- or amino acid-deprivation and hyperosmotic stress induce a fast cell shrinkage (with marked decrease of the intracellular water volume) associated to mTOR-dependent S6K1 dephosphorylation. Using cultured Jurkat cells, we have measured the changes of cell content and intracellular concentration of ATP, of relevant amino acids (BCAA) and of ninhydrin-positive substances (NPS, as measure of NH(2)-bearing organic osmolytes) under conditions that deactivate (leucine-deprivation, glutamine-deprivation, amino acid withdrawal, sorbitol-induced hyperosmotic stress) or reactivate a previously deactivated, mTOR-S6K1 pathway. We have also assessed the mitochondrial function by measurements of mitochondrial transmembrane potential in cells subjected to hypertonic stress. Our results indicate that diverse control signals converge on the mTOR-S6K1 signaling pathway. In the presence of adequate energy resources, the pathway senses the amino acid availability as inward transport of effective amino acids (as BCAA and especially leucine), but its activation occurs only in the presence of an extracellular amino acid complement, with glutamine as obligatory component, and does not tolerate decrements of cell water volume incapable of maintaining adequate intracellular physicochemical conditions.

Adenosine Triphosphate↗
PubMed2006

Expression of mTOR signaling pathway markers in prostate cancer progression.

BACKGROUND: The PI3K/AKT/mTOR pathway is central to prostate cancer progression. A preliminary investigation of immuno-histochemical expression of mammalian target of rapamycin (mTOR) pathway markers was undertaken to identify patterns of expression in prostate tissue. METHODS: Immunohistochemistry was performed on a custom-made prostate tissue array. Mean long scores and variability of long scores for each marker were recorded for normal lumenal cells, prostate intraepithelial neoplasia (PIN), and cancer. RESULTS: Expression of PTEN decreased and mTOR signaling pathway markers increased in PIN and in cancer as compared to normal cells in the majority of samples. Overexpression of 4E-BP1 and p-4E-BP1 was observed in PIN and cancer. However, in cancer, the overexpression of 4E-BP1 was significantly higher than with any other marker. DISCUSSION: Results suggest that 4E-BP1 overexpression is strongly associated with prostate cancer, especially when combined with PTEN and mTOR expression data. Hierarchical clustering analysis utilizing PTEN, mTOR, and 4E-BP1 separated normal from cancer cell populations in most cases.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Role of mTOR signalling in the control of translation initiation and elongation by nutrients.

Protein synthesis requires nutrients both as precursors (amino acids) and as a source of energy, since this process consumes a high proportion of cellular metabolic energy. Recent work has shown that both types of nutrients directly influence the activities of components of the translational machinery in mammalian cells. Amino acids positively regulate signalling through the mammalian target of the rapamycin (mTOR) pathway, although the degree of dependency on external amino acids varies between cell types. mTOR signalling modulates several key components involved in mRNA translation, in particular (via repressor proteins) the cap-binding initiation factor eIF4E, the ribosomal protein S6 kinases, and elongation factor eEF2. The branched-chain amino acid leucine is the most effective one in most cell types. It is currently unclear how mammalian cells sense prevailing amino acid levels, although this may involve intracellular amino acids. Cellular ATP levels can also influence mTOR activity. The activities of some translation factors are modulated by mTOR-independent mechanisms. Examples include the regulation of eEF2 by cellular energy levels, which may be controlled via the AMP-activated protein kinase, and the activity of the guanine nucleotide-exchange factor eIF2B, which is modulated by amino acids and metabolic fuels.

Amino Acids↗
PubMed2005

PKCdelta and mTOR interact to regulate stress and IGF-I induced IRS-1 Ser312 phosphorylation in breast cancer cells.

IRS-1 (Insulin Receptor Substrate-1) is an adaptor protein important for insulin and IGF-I receptor (Insulin-like Growth Factor-IR) transduction to downstream targets. One mechanism recently identified to downregulate IGF-I or insulin receptor signaling in diabetic models is IRS-1 Ser(312) phosphorylation. To date, the importance of this residue in cancer is unknown. This paper identifies mechanisms leading to Ser(312) regulation in MCF-7 breast cancer cells. Whereas IGF-I phosphorylation of IRS(312) is PI (phosphatidylinositol) 3-kinase dependent, anisomycin stress treatment requires JNK activation to induce phosphorylation of IRS(312). We show that both IGF-I and anisomycin stress treatment converge downstream onto mTOR (Mammalian Target of Rapamycin) and PKCdelta (Protein Kinase C-delta) to induce IRS-1 Ser(312) phosphorylation. mTOR associates with IRS-1 and is primarily required for Ser(312) phosphorylation in response to stress or IGF-I treatment. PKCdelta binds to mTOR and its activity is also important for stress or IGF-I mediated Ser(312) phosphorylation. Thus, mTOR and PKCdelta convey diverse signals to regulate IRS-1 function.

Anisomycin↗
PubMed2005

Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice.

Early diabetic nephropathy is characterized by renal hypertrophy that is mainly due to proximal tubular hypertrophy. Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase, and its signaling has been reported to regulate protein synthesis and cellular growth, specifically, hypertrophy. Therefore, we examined the effect of mTOR signaling on diabetic renal hypertrophy by using the specific inhibitor for mTOR, rapamycin. Ten days after streptozotocin-induced diabetes, mice showed kidney hypertrophy with increases in the phosphorylation of p70S6kinase and the expression of cyclin kinase inhibitors, p21(Cip1) and p27(Kip1), in the kidneys. The intraperitoneal injection of rapamycin (2 mg/kg/day) markedly attenuated the enhanced phosphorylation of p70S6kinase, the increment of cyclin-dependent kinase inhibitors, and renal enlargement without any changes of clinical parameters, including blood glucose, blood pressure, and food intake. Overexpression of a constitutive active form of p70S6kinase resulted in increased cell size of cultured mouse proximal tubule cells; thus, activation of p70S6kinase causes hypertrophy of proximal tubular cells. Our findings suggest that activation of mTOR signaling causes renal hypertrophy at the early stage of diabetes.

Animals↗
PubMed2006

Role of the phosphatidylinositol 3-kinase and mTOR pathways in the regulation of renal fibroblast function and differentiation.

Tubulointerstitial fibrosis is largely mediated by (myo)fibroblasts present in the interstitium. In this study, we investigated the role of mTOR and phosphatidylinositol 3-kinase in the regulation of fibroblast kinetics, fibroblast differentiation, and collagen synthesis. Rat renal fibroblasts were propagated from kidneys 3 days post-ureteric obstruction and specific inhibitors of mTOR (RAD) and phosphatidylinositol 3-kinase (LY294002) were used to examine the regulation of fibrogenesis. LY294002 but not RAD completely inhibited phosphorylation of Akt, while both inhibitors decreased phosphorylation of the S6 ribosomal protein. RAD and LY decreased foetal calf serum stimulated proliferation and DNA synthesis. In addition to their individual effects, treatment with both RAD and LY294002 decreased serum-induced fibroblast proliferation and DNA synthesis significantly more than either drug alone. TUNEL positive cells (apoptosis) in RAD and LY294002 treated groups were not different from control groups. In addition to their effect on proliferation, both inhibitors also reduced total collagen synthesis. Differentiation studies indicated an increase in alpha-smooth muscle actin expression relative to beta-actin (western blotting), with cytochemistry confirming that all doses of RAD and LY294002 increased the proportion of alpha-smooth muscle actin positive cells, and hence myofibroblasts. Effects were independent of cell toxicity. These results highlight the potential significance of PI3K and mTOR, in the regulation of renal (myo)fibroblast activity. The synergistic effects of LY and RAD on proliferation suggest that mTOR signalling involves pathways other than phosphatidylinositol 3-kinase. These results provide a novel insight into the mechanisms of fibroblast regulation during fibrogenesis.

Actins↗
PubMed2005

The Akt-mTOR tango and its relevance to cancer.

The downstream effector of PI3K, Akt, is frequently hyperactivated in human cancers. A critical downstream effector of Akt, which contributes to tumorigenesis, is mTOR. In the PI3K/Akt/mTOR pathway, Akt is flanked by two tumor suppressors: PTEN, acting as a brake upstream of Akt, and TSC1/TSC2 heterodimer, acting as a brake downstream of Akt and upstream of mTOR. In the absence of the TSC1/TSC2 brake, mTOR activity is unleashed to inhibit Akt via an inhibitory feedback mechanism. Two recent studies used mouse genetics to assess the roles of PTEN and TSC2 in cancer, underscoring the importance of Akt-mTOR interplay for cancer progression and therapy.

Animals↗
PubMed2005

mTOR--beyond transplantation.

mTOR kinase plays a central role in the activation of many cell types, and blocking mTOR function with rapamycin results in arrest of the cell cycle at the G1 phase. Recently, several additional molecules have been identified in the mTOR pathway, providing further opportunities to interfere with cell activation and develop novel therapeutic agents. Under certain conditions and in specific cell types, activation can occur independently of mTOR and in the presence of rapamycin. Selective inhibition of cell activation in the appropriate setting might prove to be beneficial for several autoimmune or inflammatory diseases.

Autoimmune Diseases↗
PubMed2006

mTOR signaling in the hippocampus is necessary for memory formation.

It is widely accepted that the formation of long-term memory (LTM) requires mRNA translation, but little is known about the cellular mechanisms in the brain that regulate this process. Mammalian target of rapamycin (mTOR) is a key regulator of translational efficacy and capacity. Here, we show that LTM formation of one-trial inhibitory avoidance (IA) in rats, a hippocampus-dependent fear-motivated learning task, requires mTOR activation. IA training is specifically associated with a rapid increase in the phosphorylation state of mTOR and its substrate ribosomal S6 kinase (p70S6K). Bilateral intra-CA1 infusion of rapamycin, a selective mTOR inhibitor, 15 min before, but not immediately after training completely hinders IA LTM without affecting short-term memory (STM) retention. Therefore, our findings indicate that the regulation of hippocampal mRNA translation is a major control step in memory consolidation.

Analysis of Variance↗
PubMed2004

TSC2: filling the GAP in the mTOR signaling pathway.

The tumor-suppressor proteins TSC1 and TSC2 are associated with an autosomal dominant disorder known as tuberous sclerosis complex (TSC). TSC1 and TSC2 function as a heterodimer to inhibit cell growth and proliferation. Another protein, mTOR (mammalian target of rapamycin), is regarded as a central controller of cell growth in response to growth factors, cellular energy and nutrient levels. Recent breakthroughs in TSC research link the TSC1/2 heterodimer protein to the mTOR signaling network. It has recently been shown that TSC2 has GTPase-activating protein (GAP) activity towards the Ras family small GTPase Rheb (Ras homolog enriched in brain), and TSC1/2 antagonizes the mTOR signaling pathway via stimulation of GTP hydrolysis of Rheb. Thus, TSC1/2 and Rheb have pivotal roles in mediating growth factors, nutrient and energy sensing signals to mTOR-dependent targets. These discoveries lend new insight into TSC pathogenesis.

Animals↗
PubMed2006

Effects of a combined treatment with mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer cells.

OBJECTIVE: Interactions between estrogen receptor signaling and the PI3K/Akt pathway are present in estrogen-dependent cancer cells. Therapeutical inhibition of each of these pathways has been proven to exert antitumoral effects. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of Akt, is able to restore tamoxifen response in tamoxifen-resistant breast cancer cells. Given that Akt and mTOR phosphorylation also is frequently detected in ovarian and endometrial cancer, we intended to find out to what extent mTOR inhibitor RAD001 (everolimus) and tamoxifen add to each other's effects on growth and apoptosis of cancer cell lines derived from these tissues when given concomitantly. METHODS: OVCAR-3 and SK-OV-3 ovarian cancer cells, HEC-1A endometrial adenocarcinoma cells and MCF-7 breast cancer cells were treated with different concentrations of mTOR inhibitor RAD001 alone or in combination with 4-OH tamoxifen. Relative numbers of viable cells were assessed by means of the resazurin-based Cell Titer Blue assay, cellular apoptosis was examined by measurement of activated caspases 3 and 7 by means of the luminometric Caspase-Glo assay. RESULTS: Treatment with RAD001 resulted in growth inhibition of all employed cancer cell lines in a dose-dependent manner, and SK-OV-3 ovarian cancer cells proved to be most sensitive to this drug. Moreover, we report the observation of additive, but not synergistical growth inhibitory effects of a combination treatment with RAD001 and 4-OH TAM on SK-OV-3 and OVCAR-3 ovarian cancer cells and MCF-7 breast cancer cells in vitro, whereas no such effect was observed in HEC-1A endometrial adenocarcinoma cells. Combination treatment with both drugs was demonstrated to be superior to single treatment with lower concentrations (0.1 and 1 nM) of RAD001 or standard concentrations of 4-OH TAM. Furthermore, RAD001 increased the apoptotic effect triggered by high 4-OH TAM concentrations in SK-OV-3 ovarian cancer cells. CONCLUSION: Combination treatment with RAD001 and 4-OH TAM in vitro exerts an additive antitumoral effect on ovarian cancer cells and MCF-7 breast cancer cells. The significance of these data in the clinical situation has to be evaluated in further studies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

TSC2 regulates VEGF through mTOR-dependent and -independent pathways.

Inactivation of the TSC2 tumor suppressor protein causes tuberous sclerosis complex (TSC), a disease characterized by highly vascular tumors. TSC2 has multiple functions including inhibition of mTOR (mammalian target of Rapamycin). We found that TSC2 regulates VEGF through mTOR-dependent and -independent pathways. TSC2 loss results in the accumulation of HIF-1alpha and increased expression of HIF-responsive genes including VEGF. Wild-type TSC2, but not a disease-associated TSC2 mutant, downregulates HIF. Rapamycin normalizes HIF levels in TSC2(-/-) cells, indicating that TSC2 regulates HIF by inhibiting mTOR. In contrast, Rapamycin only partially downregulates VEGF in this setting, implying an mTOR-independent link between TSC2 loss and VEGF. This pathway may involve chromatin remodeling since the HDAC inhibitor Trichostatin A downregulates VEGF in TSC2(-/-) cells.

Animals↗
PubMed2006

PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR.

Loss of the promyelocytic leukaemia (PML) tumour suppressor has been observed in several human cancers. The tumour-suppressive function of PML has been attributed to its ability to induce growth arrest, cellular senescence and apoptosis. Here we identify PML as a critical inhibitor of neoangiogenesis (the formation of new blood vessels) in vivo, in both ischaemic and neoplastic conditions, through the control of protein translation. We demonstrate that in hypoxic conditions PML acts as a negative regulator of the synthesis rate of hypoxia-inducible factor 1alpha (HIF-1alpha) by repressing mammalian target of rapamycin (mTOR). PML physically interacts with mTOR and negatively regulates its association with the small GTPase Rheb by favouring mTOR nuclear accumulation. Notably, Pml-/- cells and tumours display higher sensitivity both in vitro and in vivo to growth inhibition by rapamycin, and lack of PML inversely correlates with phosphorylation of ribosomal protein S6 and tumour angiogenesis in mouse and human tumours. Thus, our findings identify PML as a novel suppressor of mTOR and neoangiogenesis.

Animals↗
PubMed2005

Atrophy of S6K1(-/-) skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control.

The mammalian target of rapamycin (mTOR) and Akt proteins regulate various steps of muscle development and growth, but the physiological relevance and the downstream effectors are under investigation. Here we show that S6 kinase 1 (S6K1), a protein kinase activated by nutrients and insulin-like growth factors (IGFs), is essential for the control of muscle cytoplasmic volume by Akt and mTOR. Deletion of S6K1 does not affect myoblast cell proliferation but reduces myoblast size to the same extent as that observed with mTOR inhibition by rapamycin. In the differentiated state, S6K1(-/-) myotubes have a normal number of nuclei but are smaller, and their hypertrophic response to IGF1, nutrients and membrane-targeted Akt is blunted. These growth defects reveal that mTOR requires distinct effectors for the control of muscle cell cycle and size, potentially opening new avenues of therapeutic intervention against neoplasia or muscle atrophy.

Animals↗
PubMed2003

Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/- compound mutant mice.

The mammalian homeobox transcription factor CDX2 has key roles in intestinal development and differentiation. Heterozygous Cdx2 mice develop one or two benign hamartomas in the proximal colon, whereas heterozygous Apc(Delta716) mice develop numerous adenomatous polyps, mostly in the small intestine. Here we show that the colonic polyp number is about six times higher in Apc+/Delta716 Cdx2+/- compound mutant mice. Levels of both APC and CDX2 were significantly lower in the distal colon, which caused high anaphase bridge index (ABI) associated with a higher frequency of loss of heterozygosity (LOH) at Apc. In cultured rat intestinal epithelial and human colon cancer cell lines, suppression of CDX2 by antisense RNA caused marked increases in ABI and chromosomal aberrations. This was mediated by stimulation of the mTOR pathway, causing translational deregulation and G1-S acceleration, associated with low levels of p27 and activation of cyclin E-Cdk2. We obtained similar results in the colonic mucosa of Apc+/Delta716) Cdx2+/- compound mutant mice. Forced activation of mTOR through upstream regulator Akt also increased ABI in colon cancer cells. High ABI in all cell lines was suppressed by mTOR inhibitors LY294002 and rapamycin. These results suggest that reduced expression of CDX2 is important in colon tumorigenesis through mTOR-mediated chromosomal instability.

Adenomatous Polyposis Coli Protein↗