The Mammalian Target of Rapamycin Pathway as a Potential Target for Cancer Chemoprevention (original) (raw)
Rapamycin regulates biochemical metabolites
2013
the mammalian target of rapamycin (mtOr) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth, and deregulation of this pathway is associated with tumorigenesis. p53, and its less investigated family member p73, have been shown to interact closely with mtOr pathways through the transcriptional regulation of different target genes. to investigate the metabolic changes that occur upon inhibition of the mtOr pathway and the role of p73 in this response primary mouse embryonic fibroblast from control and tAp73 −/− were treated with the macrocyclic lactone rapamycin. extensive gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS/MS) analysis were used to obtain a rapamycin-dependent global metabolome profile from control or tAp73 −/− cells. In total 289 metabolites involved in selective pathways were identified; 39 biochemical metabolites were found to be significantly altered, many of which are known to be associated with the cellular stress response.
Mechanistic target of rapamycin inhibitors: successes and challenges as cancer therapeutics
Cancer Drug Resistance, 2019
Delineating the contributions of specific cell signalling cascades to the development and maintenance of tumours has greatly informed our understanding of tumorigenesis and has advanced the modern era of targeted cancer therapy. It has been revealed that one of the key pathways regulating cell growth, the phosphatidylinositol 3-kinase/mechanistic target of rapamycin (PI3K/mTOR) signalling axis, is commonly dysregulated in cancer. With a specific, well-tolerated inhibitor of mTOR available, the impact of inhibiting this pathway at the level of mTOR has been tested clinically. This review highlights some of the promising results seen with mTOR inhibitors in the clinic and assesses some of the challenges that remain in predicting patient outcome following mTOR-targeted therapy.
International Journal of Molecular Sciences, 2013
The mammalian target of rapamycin (mTOR) is a critical regulator of many fundamental features in response to upstream cellular signals, such as growth factors, energy, stress and nutrients, controlling cell growth, proliferation and metabolism through two complexes, mTORC1 and mTORC2. Dysregulation of mTOR signalling often occurs in a variety of human malignant diseases making it a crucial and validated target in the treatment of cancer. Tumour cells have shown high susceptibility to mTOR inhibitors. Rapamycin and its derivatives (rapalogs) have been tested in clinical trials in several tumour types and found to be effective as anticancer agents in patients with advanced cancers. To block mTOR function, they form a complex with FKBP12 and then bind the FRB domain of mTOR. Furthermore, a new generation of mTOR inhibitors targeting ATP-binding in the catalytic site of mTOR showed potent and more selective inhibition. More recently, microRNAs (miRNA) have emerged as modulators of biological pathways that are essential in cancer initiation, development and progression. Evidence collected to date shows that miRNAs may function as tumour suppressors or oncogenes in several human neoplasms. The mTOR pathway is a promising target by miRNAs for anticancer therapy. Extensive studies have indicated that regulation of the mTOR pathway by miRNAs plays a major role in cancer progression, indicating a novel way to investigate the tumorigenesis and therapy of cancer. Here, we summarize current findings of the role of
Oncogene, 2004
Cell growth (an increase in cell mass and size through macromolecular biosynthesis) and cell cycle progression are generally tightly coupled, allowing cells to proliferate continuously while maintaining their size. The target of rapamycin (TOR) is an evolutionarily conserved kinase that integrates signals from nutrients (amino acids and energy) and growth factors (in higher eukaryotes) to regulate cell growth and cell cycle progression coordinately. In mammals, TOR is best known to regulate translation through the ribosomal protein S6 kinases (S6Ks) and the eukaryotic translation initiation factor 4Ebinding proteins. Consistent with the contribution of translation to growth, TOR regulates cell, organ, and organismal size. The identification of tumor suppressor protein tuberous sclerosis1/2 and Ras-homolog enriched in brain has biochemically linked the TOR and phosphatidylinositol 3-kinase (PI3K) pathways, providing a mechanism for the crosstalk that occurs between these pathways. TOR is emerging as a novel antitumor target, since the TOR inhibitor rapamycin appears to be effective against tumors resulting from aberrantly high PI3K signaling. Not only may inhibition of TOR be effective in cancer treatment, but rapamycin is an FDA-approved immunosuppressive and cardiology drug. We review here what is known (and not known) about the function of TOR in cellular and animal physiology.
2010
The apoptotic mode of cell death (programmed cell death) is an active and defined process that plays an important role in the development of multicellular organisms and in the regulation and maintenance of cell populations in tissues under physiologic and pathologic conditions. Since dysregulation of apoptosis is associated with the progress of many diseases, induction of apoptosis is an interesting pharmacological target for the therapy of many diseases. Our study shows that the novel semisynthetic pentacyclic triterpenoid C-KβBA has a profound antiproliferative effect on different tumor cell lines and that it induces apoptosis of tumor cells in vitro and vivo. Previous studies have shown that the mammalian target of rapamycin (mTOR) is a key regulator for many cells activities, and that the perturbation of this signaling pathway is implicated in many diseases and metabolic disorders. Accordingly targeting the mTOR signaling pathway seems to be a promising therapeutic approach for ...
Leukemia, 2005
The mammalian target of rapamycin (mTOR) pathway plays important roles in regulating nutrient metabolism and promoting the growth and survival of cancer cells, which exhibit increased glycolysis for ATP generation. In this study, we tested the hypothesis that inhibition of the mTOR pathway and glycolysis would synergistically impact the energy metabolism in cancer cells and may serve as an effective therapeutic strategy to kill malignant cells. Using human lymphoma cells and leukemia cells, we demonstrated that the combination of rapamycin, an mTOR inhibitor, with a glycolytic inhibitor produced synergistic cytotoxic effect, as evidenced by apoptosis and cell growth inhibition assays. Mechanistic studies showed that inhibition of the mTOR pathway by rapamycin alone sufficiently suppressed the phosphorylation of the downstream molecules p70S6K and 4E-BP-1, but only caused a moderate cytostatic effect. Combination of mTOR inhibition and blockage of glycolysis synergistically suppressed glucose uptake and severely depleted cellular ATP pools, leading to significant enhancement of cell killing. In contrast, combination of rapamycin and ara-C did not increase cytotoxicity in vitro. Our findings suggest that targeting mTOR pathway in combination with inhibition of glycolysis may be an effective therapeutic strategy for hematological malignancies. This mechanismbased drug combination warrants further investigation in preclinical and clinical settings.
mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin
Introduction: The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) protein kinase promotes cell growth by controlling major anabolic and catabolic processes in response to a variety of environmental and intracellular stimuli and is deregulated in aging and human diseases such as cancer and diabetes. Rapamycin, an allosteric inhibitor of mTORC1, is used clinically in organ transplanta-tion and the treatment of certain cancers. Exactly how rapamycin perturbs mTORC1 signaling is poorly understood, and it remains unknown why certain mTORC1 phosphorylation sites are sensitive to the drug, whereas others are not. Here, we test the hypothesis that the inherent capacity of a phosphoryla-tion site to serve as an mTORC1 substrate (a property we call substrate quality) is a key determinant of its sensitivity to rapamycin as well as nutrient and growth factor starvation.
Mechanistic/mammalian target of rapamycin: Recent pathological aspects and inhibitors
Medicinal research reviews, 2018
The mechanistic/mammalian target of rapamycin (mTOR), also known as the mechanistic target of rapamycin, regulates many normal cell processes such as transcription, cell growth, and autophagy. Overstimulation of mTOR by its ligands, amino acids, sugars, and/or growth factors leads to physiological disorders, including cancer and neurodegenerative diseases. In this study, we reviewed the recent advances regarding the mechanism that involves mTOR in cancer, aging, and neurodegenerative diseases. The chemical and biological properties of recently reported small molecules that function as mTOR kinase inhibitors, including adenosine triphosphate-competitive inhibitors and dual mTOR/PI3K inhibitors, have also been reviewed. We focused on the reports published in the literature from 2012 to 2017.
Cancer Cell International
Background: Glioma is the most common highly aggressive, primary adult brain tumour. Clinical data show that therapeutic approaches cannot reach the expectations in patients, thus gliomas are mainly incurable diseases. Tumour cells can adapt rapidly to alterations during therapeutic treatments related to their metabolic rewiring and profound heterogeneity in tissue environment. Renewed interests aim to develop effective treatments targeting angiogenesis, kinase activity and/or cellular metabolism. mTOR (mammalian target of rapamycin), whose hyperactivation is characteristic for many tumours, promotes metabolic alterations, macromolecule biosynthesis, cellular growth and survival. Unfortunately, mTOR inhibitors with their lower toxicity have not resulted in appreciable survival benefit. Analysing mTOR inhibitor sensitivity, other metabolism targeting treatments and their combinations could help to find potential agents and biomarkers for therapeutic development in glioma patients. Methods: In vitro proliferation assays, protein expression and metabolite concentration analyses were used to study the effects of mTOR inhibitors, other metabolic treatments and their combinations in glioma cell lines. Furthermore, mTOR activity and cellular metabolism related protein expression patterns were also investigated by immunohistochemistry in human biopsies. Temozolomide and/or rapamycin treatments altered the expressions of enzymes related to lipid synthesis, glycolysis and mitochondrial functions as consequences of metabolic adaptation; therefore, other anti-metabolic drugs (chloroquine, etomoxir, doxycycline) were combined in vitro. Results: Our results suggest that co-targeting metabolic pathways had tumour cell dependent additive/synergistic effects related to mTOR and metabolic protein expression patterns cell line dependently. Drug combinations, especially rapamycin + doxycycline may have promising anti-tumour effect in gliomas. Additionally, our immunohistochemistry results suggest that metabolic and mTOR activity alterations are not related to the recent glioma classification, and these protein expression profiles show individual differences in patients' materials. Conclusions: Based on these, combinations of different new/old drugs targeting cellular metabolism could be promising to inhibit high adaptation capacity of tumour cells depending on their metabolic shifts. Relating to this, such a development of current therapy needs to find special biomarkers to characterise metabolic heterogeneity of gliomas.