Explore the vast range of titles available.

Hepatocellular carcinoma features extensive metabolic reprogramming. This includes alterations in major biochemical pathways such as glycolysis, the pentose phosphate pathway, amino acid metabolism and fatty acid metabolism. Moreover, there is a complex interplay among these altered pathways, particularly involving acetyl-CoA (coenzyme-A) metabolism and redox homeostasis, which in turn influences reprogramming of other metabolic pathways. Understanding these metabolic changes and their interactions with cellular signaling pathways offers potential strategies for the targeted treatment of hepatocellular carcinoma and improved patient outcomes. This review explores the specific metabolic alterations observed in hepatocellular carcinoma and highlights their roles in the progression of the disease. Glycolysis shift fuels liver cancer growth and resistance Cancer cells often change their metabolism to support rapid growth. This study examines how liver cancer, specifically hepatocellular carcinoma (HCC), alters its metabolism and explores potential treatments. The authors focus on how HCC cells use glucose, amino acids and fatty acids differently from normal cells. HCC cells rely heavily on glycolysis even when oxygen is present, a phenomenon known as the Warburg effect. They also activate the pentose phosphate pathway to produce molecules needed for growth and survival. Additionally, HCC cells depend on certain amino acids such as glutamine and serine for building blocks and energy. This study highlights that targeting these altered metabolic pathways could be a promising strategy for treating HCC. In conclusion, understanding these metabolic changes in HCC can lead to new treatment approaches. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

TOR (Target Of Rapamycin) is a highly conserved protein kinase that is important in both fundamental and clinical biology. In fundamental biology, TOR is a nutrient-sensitive, central controller of cell growth and aging. In clinical biology, TOR is implicated in many diseases and is the target of the drug rapamycin used in three different therapeutic areas. The yeast Saccharomyces cerevisiae has played a prominent role in both the discovery of TOR and the elucidation of its function. Here we review the TOR signaling network in S. cerevisiae.

Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase and a master regulator of cell growth and metabolism, forms two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. While mTORC1 signaling is well characterized, mTORC2 is relatively poorly understood. mTORC2 appears to exist in functionally distinct pools, but few mTORC2 effectors/substrates have been identified. Here, we review recent advances in our understanding of mTORC2 signaling, with particular emphasis on factors that control mTORC2 activity.

The evolutionarily conserved target of rapamycin complex 1 （TORC1） is a master regulator of cell growth and metabolism. In mammals, growth factors and cellular energy stimulate mTORC1 activity through inhibition of the TSC complex （TSC1-TSC2-TBC1D7）, a negative regulator of mTORC1. Amino acids signal to mTORC1 independently of the TSC complex. Here, we review recently identified regulators that link amino acid sufficiency to mTORC1 activity and how mutations affecting these regulators cause human disease.

Key Points TOR (target of rapamycin) is a Ser/Thr kinase that is present in all eukaryotes. It integrates various stresses and various inputs that are indicative of cellular energy and nutrient status, and then signals to control cellular growth, translation, metabolism and survival. TOR forms two structurally and functionally distinct complexes — the rapamycin-sensitive TOR complex 1 (TORC1) and the rapamycin-insensitive TORC2 — each of which regulates different cellular responses. Many components within the mammalian TOR (mTOR) signalling network are tumour suppressors or oncogenes, and TOR signalling is frequently dysregulated in cancer. mTOR also plays an important part in the control of whole-body metabolism, and its overactivation by excessive nutrient intake is implicated in the development of diabetes. Pharmacological downregulation of TOR signalling has also been shown to mimic the effects of dietary restriction to prolong lifespan in yeast, worms, flies and mice. Rapamycin and its derivatives (collectively known as rapalogues) have been clinically approved for some cancer indications. They bind TOR allosterically in complex with FK506-binding protein 12 (FKBP12) to inhibit TORC1 activity. Nevertheless, the absence of broad clinical effectiveness is surprising given the central role of TOR signalling, and suggests that the full therapeutic potential of TOR inhibition is not being exploited. This has spurred the development of ATP-competitive inhibitors of TOR kinase activity. These compounds hold the promise of providing more comprehensive and sustained TORC1 inhibition than rapamycin, in addition to inhibition of TORC2 activity. Owing to TOR's similarity to phosphoinositide 3-kinase (PI3K), many ATP-competitive TOR inhibitors also target PI3K activity. This allows classification into: dual mTOR/PI3K inhibitors (both kinases inhibited at similar effective concentrations) and pan-mTOR inhibitors (greater selectivity for mTOR over PI3K). The ATP-competitive TOR inhibitors are generally superior to rapamycin in inhibiting tumour proliferation in preclinical models, and several are in Phase I clinical trials. Nevertheless, there are concerns as to their toxicity and eventual clinical efficacy. Mammalian target of rapamycin (mTOR) has a central role in controlling cellular growth and metabolism. Hall and colleagues describe the advances in therapeutic targeting of this protein, and discuss their potential for the treatment of cancer and beyond. Mammalian target of rapamycin (mTOR) is an atypical protein kinase that controls growth and metabolism in response to nutrients, growth factors and cellular energy levels, and it is frequently dysregulated in cancer and metabolic disorders. Rapamycin is an allosteric inhibitor of mTOR, and was approved as an immuno-suppressant in 1999. In recent years, interest has focused on its potential as an anticancer drug. However, the performance of rapamycin and its analogues (rapalogues) has been undistinguished despite isolated successes in subsets of cancer, suggesting that the full therapeutic potential of targeting mTOR has yet to be exploited. A new generation of ATP-competitive inhibitors that directly target the mTOR catalytic site display potent and comprehensive mTOR inhibition and are in early clinical trials.

The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of growth. Mammalian TOR complex 2 (mTORC2) regulates AGC kinase family members and is implicated in various disorders, including cancer and diabetes. Here we report that mTORC2 is localized to the endoplasmic reticulum (ER) subcompartment termed mitochondria-associated ER membrane (MAM). mTORC2 localization to MAM was growth factor-stimulated, and mTORC2 at MAM interacted with the IP ₃ receptor (IP3R)-Grp75–voltage-dependent anion-selective channel 1 ER-mitochondrial tethering complex. mTORC2 deficiency disrupted MAM, causing mitochondrial defects including increases in mitochondrial membrane potential, ATP production, and calcium uptake. mTORC2 controlled MAM integrity and mitochondrial function via Akt mediated phosphorylation of the MAM associated proteins IP3R, Hexokinase 2, and phosphofurin acidic cluster sorting protein 2. Thus, mTORC2 is at the core of a MAM signaling hub that controls growth and metabolism.

Proteogenomic analyses of hepatocellular carcinomas (HCC) have focused on early-stage, HBV-associated HCCs. Here we present an integrated proteogenomic analysis of HCCs across clinical stages and etiologies. Pathways related to cell cycle, transcriptional and translational control, signaling transduction, and metabolism are dysregulated and differentially regulated on the genomic, transcriptomic, proteomic and phosphoproteomic levels. We describe candidate copy number-driven driver genes involved in epithelial-to-mesenchymal transition, the Wnt-β-catenin, AKT/mTOR and Notch pathways, cell cycle and DNA damage regulation. The targetable aurora kinase A and CDKs are upregulated. CTNNB1 and TP53 mutations are associated with altered protein phosphorylation related to actin filament organization and lipid metabolism, respectively. Integrative proteogenomic clusters show that HCC constitutes heterogeneous subgroups with distinct regulation of biological processes, metabolic reprogramming and kinase activation. Our study provides a comprehensive overview of the proteomic and phophoproteomic landscapes of HCCs, revealing the major pathways altered in the (phospho)proteome. Proteogenomic analyses of hepatocellular carcinomas (HCC) have focused on early-stage, HBV-associated tumours and lacked information about the phosphoproteome. Here, the authors present a comprehensive HCC proteogenomics and phosphoproteomics study in patient samples from multiple etiologies and stages.

Oncogenic signalling and metabolic alterations are interrelated in cancer cells. mTOR, which is frequently activated in cancer, controls cell growth and metabolism. mTOR signalling regulates amino acid, glucose, nucleotide, fatty acid and lipid metabolism. Conversely, metabolic inputs, such as amino acids, activate mTOR. In this Review, we discuss how mTOR signalling rewires cancer cell metabolism and delineate how changes in metabolism, in turn, sustain mTOR signalling and tumorigenicity. Several drugs are being developed to perturb cancer cell metabolism. However, their efficacy as stand-alone therapies, similar to mTOR inhibitors, is limited. Here, we discuss how the interdependence of mTOR signalling and metabolism can be exploited for cancer therapy.

The Ser-Thr kinase mammalian target of rapamycin (mTOR) controls cell growth and metabolism by stimulating glycolysis and synthesis of proteins and lipids. To further understand the central role of mTOR in cell physiology, we used quantitative phosphoproteomics to identify substrates or downstream effectors of the two mTOR complexes. mTOR controlled the phosphorylation of 335 proteins, including CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase). CAD catalyzes the first three steps in de novo pyrimidine synthesis. mTORC1 indirectly phosphorylated CAD-S1859 through S6 kinase (S6K). CAD-S1859 phosphorylation promoted CAD oligomerization and thereby stimulated de novo synthesis of pyrimidines and progression through S phase of the cell cycle in mammalian cells. Thus, mTORC1 also stimulates the synthesis of nucleotides to control cell proliferation.

Target of rapamycin (TOR), a conserved protein kinase and central controller of cell growth, functions in two structurally and functionally distinct complexes: TORC1 and TORC2. Dysregulation of mammalian TOR (mTOR) signaling is implicated in pathologies that include diabetes, cancer, and neurodegeneration. We resolved the architecture of human mTORC1 (mTOR with subunits Raptor and mLST8) bound to FK506 binding protein (FKBP)–rapamycin, by combining cryo–electron microscopy at 5.9 angstrom resolution with crystallographic studies of Chaetomium thermophilum Raptor at 4.3 angstrom resolution. The structure explains how FKBP-rapamycin and architectural elements of mTORC1 limit access to the recessed active site. Consistent with a role in substrate recognition and delivery, the conserved amino-terminal domain of Raptor is juxtaposed to the kinase active site.