Chromosomal instability (CIN) is a hallmark of human cancer, and it is associated with poor prognosis, metastasis, and therapeutic resistance. CIN results from errors in chromosome segregation during ...mitosis, leading to structural and numerical chromosomal abnormalities. In addition to generating genomic heterogeneity that acts as a substrate for natural selection, CIN promotes inflammatory signaling by introducing double-stranded DNA into the cytosol, engaging the cGAS-STING anti-viral pathway. These multipronged effects distinguish CIN as a central driver of tumor evolution and as a genomic source for the crosstalk between the tumor and its microenvironment, in the course of immune editing and evasion.
Chromosomal instability is well recognized as a hallmark of many cancers and a driver of tumor evolution. In this Perspective, Bakhoum and Cantley discuss how this instability directly impacts the tumor micro-environment via cGAS and STING-dependent signaling.
Warburg suggested that the alterations in metabolism that he observed in cancer cells were due to the malfunction of mitochondria. In the past decade, we have revisited this idea and reached a better ...understanding of the 'metabolic switch' in cancer cells, including the intimate and causal relationship between cancer genes and metabolic alterations, and their potential to be targeted for cancer treatment. However, the vast majority of the research into cancer metabolism has been limited to a handful of metabolic pathways, while other pathways have remained in the dark. This Progress article brings to light the important contribution of fatty acid oxidation to cancer cell function.
The study of normal mammalian cell growth and the defects that contribute to disease pathogenesis links metabolism to cell growth. Here, we visit several aspects of growth-promoting metabolism, ...emphasizing recent advances in our understanding of how alterations in glucose metabolism affect cytosolic and mitochondrial redox potential and ATP generation. These alterations drive cell proliferation not only through supporting biosynthesis, energy metabolism, and maintaining redox potential but also through initiating signaling mechanisms that are still poorly characterized. The evolutionary basis of these additional layers of growth control is also discussed.
mTORC1 promotes cell growth in response to nutrients and growth factors. Insulin activates mTORC1 through the PI3K-Akt pathway, which inhibits the TSC1-TSC2-TBC1D7 complex (the TSC complex) to turn ...on Rheb, an essential activator of mTORC1. However, the mechanistic basis of how this pathway integrates with nutrient-sensing pathways is unknown. We demonstrate that insulin stimulates acute dissociation of the TSC complex from the lysosomal surface, where subpopulations of Rheb and mTORC1 reside. The TSC complex associates with the lysosome in a Rheb-dependent manner, and its dissociation in response to insulin requires Akt-mediated TSC2 phosphorylation. Loss of the PTEN tumor suppressor results in constitutive activation of mTORC1 through the Akt-dependent dissociation of the TSC complex from the lysosome. These findings provide a unifying mechanism by which independent pathways affecting the spatial recruitment of mTORC1 and the TSC complex to Rheb at the lysosomal surface serve to integrate diverse growth signals.
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•Insulin triggers acute dissociation of the TSC complex from Rheb at the lysosome•Release of the TSC complex from the lysosome is required to activate mTORC1•Dissociation of TSC complex from the lysosome requires Akt phosphorylation of TSC2•The TSC complex is constitutively dissociated from the lysosome in PTEN null cells
Activation of the PI3K-Akt pathway signals to mTORC1 by stimulating release of the TSC complex from Rheb at the lysosomal surface, where mTORC1 is independently recruited through amino acid sensing mechanisms. This spatial regulation provides a mechanism to integrate growth signals upstream of mTORC1.
Obesity is a risk factor for cancer development and is associated with poor prognosis in multiple tumor types. The positive energy balance linked with obesity induces a variety of systemic changes ...including altered levels of insulin, insulin-like growth factor-1, leptin, adiponectin, steroid hormones, and cytokines. Each of these factors alters the nutritional milieu and has the potential to create an environment that favors tumor initiation and progression. Although the complete ramifications of obesity as it relates to cancer are still unclear, there is convincing evidence that reducing the magnitude of the systemic hormonal and inflammatory changes has significant clinical benefits. This review will examine the changes that occur in the obese state and review the biologic mechanisms that connect these changes to increased cancer risk. Understanding the metabolic changes that occur in obese individuals may also help to elucidate more effective treatment options for these patients when they develop cancer. Moving forward, targeted clinical trials examining the effects of behavioral modifications such as reduced carbohydrate intake, caloric restriction, structured exercise, and/or pharmacologic interventions such as the use of metformin, in obese populations may help to reduce their cancer risk.
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that exists in two separate complexes, mTORC1 and mTORC2, that function to control cell size and growth in response to growth ...factors, nutrients, and cellular energy levels. Low molecular weight GTP-binding proteins of the Rheb and Rag families are key regulators of the mTORC1 complex, but regulation of mTORC2 is poorly understood. Here, we report that Rac1, a member of the Rho family of GTPases, is a critical regulator of both mTORC1 and mTORC2 in response to growth-factor stimulation. Deletion of Rac1 in primary cells using an inducible-Cre/Lox approach inhibits basal and growth-factor activation of both mTORC1 and mTORC2. Rac1 appears to bind directly to mTOR and to mediate mTORC1 and mTORC2 localization at specific membranes. Binding of Rac1 to mTOR does not depend on the GTP-bound state of Rac1, but on the integrity of its C-terminal domain. This function of Rac1 provides a means to regulate mTORC1 and mTORC2 simultaneously.
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► The effects of Rac 1 on cell size are mediated through mTOR ► Rac1 is required for both mTORC1 and mTORC2 activity ► Rac1 regulates mTORC1 and mTORC2 independent of its binding to GTP/GDP ► Rac1 interacts directly with mTOR through the Rac1 C-terminal region
Recent advances in metabolomics and computational analysis have deepened our appreciation for the role of specific metabolic pathways in dictating cell fate. Once thought to be a mere consequence of ...the state of a cell, metabolism is now known to play a pivotal role in dictating whether a cell proliferates, differentiates or remains quiescent. Here, we review recent studies of metabolism in stem cells that have revealed a shift in the balance between glycolysis, mitochondrial oxidative phosphorylation and oxidative stress during the maturation of adult stem cells, and during the reprogramming of somatic cells to pluripotency. These insights promise to inform strategies for the directed differentiation of stem cells and to offer the potential for novel metabolic or pharmacological therapies to enhance regeneration and the treatment of degenerative disease.
Thioredoxin-interacting protein (TXNIP) is an α-arrestin family protein that is induced in response to glucose elevation. It has been shown to provide a negative feedback loop to regulate glucose ...uptake into cells, though the biochemical mechanism of action has been obscure. Here, we report that TXNIP suppresses glucose uptake directly, by binding to the glucose transporter GLUT1 and inducing GLUT1 internalization through clathrin-coated pits, as well as indirectly, by reducing the level of GLUT1 messenger RNA (mRNA). In addition, we show that energy stress results in the phosphorylation of TXNIP by AMP-dependent protein kinase (AMPK), leading to its rapid degradation. This suppression of TXNIP results in an acute increase in GLUT1 function and an increase in GLUT1 mRNA (hence the total protein levels) for long-term adaptation. The glucose influx through GLUT1 restores ATP-to-ADP ratios in the short run and ultimately induces TXNIP protein production to suppress glucose uptake once energy homeostasis is reestablished.
► TXNIP is an AMPK substrate ► TXNIP negatively regulates GLUT1 protein and mRNA levels
Otto Warburg discovered that cancer cells exhibit a high rate of glycolysis in the presence of ample oxygen, a process termed aerobic glycolysis, in 1924 (Warburg et al., 1924). Since then we have ...significantly advanced our understanding of cancers’ fuel choice to meet their demands for energy and for the production of biosynthetic precursors. In this review, we will discuss the preferred nutrients of cancer cells and how they are utilized to satisfy their bioenergetic and biosynthetic needs. In addition, we will describe how cell intrinsic and extrinsic factors such as oncogene mutations, nutrient and oxygen availability, and other microenvironmental factors influence fuel choice.
The in vivo metabolism of tumors is influenced by both cell intrinsic metabolic regulation and cell extrinsic factors in the microenvironment such as nutrient availability. This review discusses the preferred nutrients of cancer cells and how these factors influence fuel choice.
The PI3K-AKT, mTOR-p70S6 kinase and AMPK pathways play distinct and critical roles in metabolic regulation. Each pathway is necessary for leptin's anorexigenic effects in the hypothalamus. Here we ...show that these pathways converge in an integrated phosphorylation cascade to mediate leptin action in the hypothalamus. We identify serine491 on α2AMPK as the site of convergence and show that p70S6 kinase forms a complex with α2AMPK, resulting in phosphorylation on serine491. Blocking α2AMPK-serine491 phosphorylation increases hypothalamic AMPK activity, food intake, and body weight. Serine491 phosphorylation is necessary for leptin's effects on hypothalamic α2AMPK activity, neuropeptide expression, food intake, and body weight. These results identify an inhibitory AMPK kinase, p70S6 kinase, and demonstrate that AMPK is a substrate for mTOR-p70S6 kinase. This discovery has broad biologic implications since mTOR-p70S6 kinase and AMPK have multiple, fundamental and generally opposing cellular effects that regulate metabolism, cell growth, and development.
► p70S6 kinase is an inhibitory AMPK kinase that phosphorylates AMPK on serine485/491 ► Leptin inhibits hypothalamic α2AMPK activity by phosphorylating it on serine491 ► α2AMPK serine491 phosphorylation is necessary and sufficient for leptin action ► Hypothalamic PI3K-AKT, mTOR-p70S6 kinase, and AMPK converge to mediate leptin action
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