Targeting cancer metabolism: a therapeutic window opens

Altered cell metabolism is a characteristic feature of many cancers. Aside from well-described changes in nutrient consumption and waste excretion, altered cancer cell metabolism also results in changes to intracellular metabolite concentrations. Increased levels of metabolites that result directly from genetic mutations and cancer-associated modifications in protein expression can promote cancer initiation and progression. Changes in the levels of specific metabolites, such as 2-hydroxyglutarate, fumarate, succinate, aspartate and reactive oxygen species, can result in altered cell signalling, enzyme activity and/or metabolic flux. In this Review, we discuss the mechanisms that lead to changes in metabolite concentrations in cancer cells, the consequences of these changes for the cells and how they might be exploited to improve cancer therapy.

Why Cancer & Metabolism? Why now?

Cell culturing on different synthetic biomaterials would reprogram cell metabolism for adaption to their living conditions because such alterations in cell metabolism were necessary for cellular functions on them. Here we used metabolomics to uncover metabolic changes when liver cells were cultured on insulin-like growth factor (IGF)/tumor necrosis factor-α (TNF-α) and chargeable polymers co-modified biomaterials with the aim to explain their modulating effects on cell metabolism. The results showed that cell metabolism on IGF-1/TNF-α co-immobilized conjugates was significantly regulated according to their scatterings on the score plot of principal component analysis. Specifically, cell metabolisms were reprogrammed to the higher level of pyrimidine metabolism, β-alanine metabolism, and pantothenate and CoA biosynthesis, and the lower level of methionine salvage pathway in order to promote cell growth on IGF/TNF-α co-modified surface. Furthermore, cell senescence on PSt-PAAm-IGF/TNF-α surface was delayed through the regulation of branch amino acid metabolism and AMPK signal pathway. The research showed that metabolomics had great potential to uncover the molecular interaction between biomaterials and seeded cells, and provide the insights about cell metabolic reprogramming on IGF/TNF-α co-modified conjugates for cell growth.

Hepatocyte nuclear factors play an important role in the pathogenesis of nephropathy

mTOR/AMPK signaling in the brain: Cell metabolism, proteostasis and survival

Suppression of TRIP13 Induces Metabolic Changes and Potentiates Ferroptosis in Multiple Myeloma

Metabolism in cancer cells is different from many normal cells. We have argued that alterations in cell metabolism associated with cancer may be selected to meet the distinct metabolic needs of proliferation. Unlike metabolism in differentiated cells, which is geared toward efficient ATP generation, the metabolism in cancer cells must be adapted to facilitate the accumulation of biomass. Pancreatic cancer cells are no exception, however it remains unclear exactly how the metabolism of pancreatic tumors is altered to support their growth. All cancer cells divert a larger fraction of their nutrient metabolism to pathways other than mitochondrial ATP production regardless of oxygen availability. Nevertheless, oxygen levels still influence how nutrients are metabolized. We have found that the source of carbon used in various anabolic processes can differ based on the cellular context and environmental conditions. There is strong selection for use of the M2 isoform of pyruvate kinase (PKM2) to metabolize glucose in pancreatic cancer cell lines. However, evidence suggests that PK-M2 can be dispensable for glucose metabolism by tumors in vivo. Paradoxically, high pyruvate kinase activity can suppress tumor growth, and pyruvate kinase activation can promote a catabolic state. These findings suggest a framework to consider how metabolism could be targeted for improved pancreatic cancer therapy. Citation Format: Matthew Vander Heiden. Regulation of metabolism to support tumor growth. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr IA15.

Targeted reversal and phosphorescence lifetime imaging of cancer cell metabolism via a theranostic rhenium(I)-DCA conjugate

Rhabdomyosarcoma exhibits tumor‐specific energy metabolic changes that include the Warburg effect. Since targeting cancer metabolism is a promising therapeutic approach, we examined the antitumor effects of suppressing lipid metabolism in rhabdomyosarcoma. We suppressed lipid metabolism in rhabdomyosarcoma cells in vitro by administering an inhibitor of malonyl‐CoA decarboxylase, which increases malonyl‐CoA and decreases fatty acid oxidation. Suppression of lipid metabolism in rhabdomyosarcoma cells decreased cell proliferation by inducing cell cycle arrest. Metabolomic analysis showed an increase in glycolysis and inactivation of the pentose phosphate pathway. Immunoblotting analysis revealed upregulated expression of the autophagy marker LC3A/B‐II due to increased phosphorylation of AMP‐activated protein kinase, a nutrient sensor. p21 protein expression level also increased. Inhibition of both lipid metabolism and autophagy suppressed tumor proliferation and increased apoptosis. In vivo studies involved injection of human Rh30 cells into the gastrocnemius muscle of 6‐week‐old female nude mice, which were divided into normal chow and low‐fat diet groups. The mice fed a low‐fat diet for 21 days showed reduced tumor growth compared to normal chow diet‐fed mice. Suppression of lipid metabolism disrupted the equilibrium of the cancer‐specific metabolism in rhabdomyosarcoma, resulting in a tumor growth‐inhibition effect. Therefore, the development of treatments focusing on the lipid dependence of rhabdomyosarcoma is highly promising.

Daño miocárdico por reperfusión

Eukaryotic organelles encapsulate defined subsets of cellular biochemical pathways. For example, beta oxidation of fatty acids occurs inside mitochondria while fatty acid chain elongation takes place on the endoplasmic reticulum membrane. Organelle membranes isolate reactions from each other and store intermediates and products, and can thus be viewed as “reaction vessels”, playing roles analogous to the reflux columns and holding tanks of a chemical factory. To develop an effective chemical manufacturing process, it is not enough to focus just on the chemistry, i.e. the reactants and solvents that directly participate in reactions. The size and design of the reaction vessels is of equal importance. Likewise, within a cell, the size of organelles will influence the rates of biochemical pathways contained within them. Organelle surface area can limit the rate of import of substrates and efflux of products, while the volume of the organelle can dictate the quantity of intermediates that can build up (Figure 1). Many key metabolic enzymes are organelle membrane proteins, and in such cases increased surface area could allow larger numbers of molecules into the membrane to increase metabolic flux. Figure 1 Organelles as reaction vessels. Substrate in cytoplasm (Sc) is imported into an organelle through its bounding membrane to provide substrate inside the organelle (So). This organellar substrate is then subjected to several enzymatic steps in the organelle ... The influence of organelle size on metabolism is indicated by the fact that in cells specialized for certain pathways, the organelles that contain these pathways are enlarged compared to other cell types. Secretory cells are an obvious example, in which the requirement for a high rate of flux of secreted proteins is met by a massive over proliferation of endoplasmic reticulum and Golgi apparatus. Other examples include enlarged lipid droplets in adipose cells, proliferation of microvilli on the surface of cells lining the intestine, increased surface area and volume of rhodopsin containing vesicles in rods versus cones, and changes in mitochondrial abundance as a function of respiratory state. If, as we hypothesize, organelle size affects metabolism and signaling, then reprogramming of organelle size could be used as a novel strategy for reprogramming cellular state and behavior, with direct applications in medicine and biotechnology. Organelle-directed medicine and biotechnology Cytopathologists diagnose cancer by visual assessment of cell geometry including organelle size. For example, enlarged nuclei in a pap test indicates early stage cervical cancer. Cytopathology texts are full of such examples, but we don’t understand why these changes occur. According to the hypothesis of this review, these changes of cell geometry in cancer arise because cells have adapted to the metabolic alterations that are a hallmark of cancer [1]. Could we attack cancer cells by reprogramming organelle size? We can distinguish two possible reasons for organelle size alteration in cancer cells, which in turn predict two possible ways that organelle targeted therapy could be useful (Figure 2). First, if organelle size is adjusted as a response to pathological alterations in cell metabolism, then if we could reprogram organelle size in a cancer cell using small molecules that target the size control pathway, the cell might die due to a mismatch between organelle size and metabolic state. Alternatively, organelle size alterations might arise from pathological alterations in signaling pathways that impinge on the size control system, and then alterations in cell metabolism or behavior would be a downstream effect of the change to organelle size. In this case, it might be possible to drive the cell back to a less malignant state by driving its organelles towards a more normal size range. Either outcome would be therapeutically useful, but so far this “organelle directed medicine” strategy has not to our knowledge been tested in any cancer model system. Figure 2 Organelle size changes in disease: two strategies for organelle directed medicine. Disease causing mutations (for example, loss of tumor suppressor genes or activation of oncogenes) cause organelle size changes that are observed by the cytopathologist. ... Reprogramming organelle size would also have applications in metabolic engineering. Increasing the size of organelles that encapsulate key steps of metabolite production, especially those involving toxic intermediates, could greatly enhance metabolite production. For example biodiesel production could be enhanced by targeting genes that control lipid droplet size [2–3] thereby enhancing the ability of the cell to store triglyceride (TG). Before we can implement or test these applications in medicine and biotechnology, we need to obtain mechanistic understanding of how organelle size is regulated.

Interferon regulatory factor-4 (IRF4) and IRF8 regulate differentiation, growth and functions of lymphoid and myeloid cells. Targeted deletion of irf8 in T cells (CD4-IRF8KO) has been shown to exacerbate colitis and experimental autoimmune uveitis (EAU), a mouse model of human uveitis. We therefore generated mice lacking irf4 in T cells (CD4-IRF4KO) and investigated whether expression of IRF4 by T cells is also required for regulating T cells that suppress autoimmune diseases. Surprisingly, we found that CD4-IRF4KO mice are resistant to EAU. Suppression of EAU derived in part from inhibiting pathogenic responses of Th17 cells while inducing expansion of regulatory lymphocytes that secrete IL-10 and/or IL-35 in the eye and peripheral lymphoid tissues. Furthermore, CD4-IRF4KO T cells exhibit alterations in cell metabolism and are defective in the expression of two Ikaros zinc-finger (IKZF) transcription factors (Ikaros, Aiolos) that are required for lymphocyte differentiation, metabolism and cell-fate decisions. Thus, synergistic effects of IRF4 and IkZFs might induce metabolic reprogramming of differentiating lymphocytes and thereby dynamically regulate relative abundance of T and B lymphocyte subsets that mediate immunopathogenic mechanisms during uveitis. Moreover, the diametrically opposite effects of IRF4 and IRF8 during EAU suggests that intrinsic function of IRF4 in T cells might be activating proinflammatory responses while IRF8 promotes expansion of immune-suppressive mechanisms.

One hundred years have passed since Warburg discovered alterations in cancer metabolism, more than 70 years since Sidney Farber introduced anti-folates that transformed the treatment of childhood leukaemia, and 20 years since metabolism was linked to oncogenes. However, progress in targeting cancer metabolism therapeutically in the past decade has been limited. Only a few metabolism-based drugs for cancer have been successfully developed, some of which are in — or en route to — clinical trials. Strategies for targeting the intrinsic metabolism of cancer cells often did not account for the metabolism of non-cancer stromal and immune cells, which have pivotal roles in tumour progression and maintenance. By considering immune cell metabolism and the clinical manifestations of inborn errors of metabolism, it may be possible to isolate undesirable off-tumour, on-target effects of metabolic drugs during their development. Hence, the conceptual framework for drug design must consider the metabolic vulnerabilities of non-cancer cells in the tumour immune microenvironment, as well as those of cancer cells. In this Review, we cover the recent developments, notable milestones and setbacks in targeting cancer metabolism, and discuss the way forward for the field.

High-risk HPV infection accounts for 99.7% of cervical cancer, over 90% of anal cancer, 50% of head and neck cancers, 40% of vulvar cancer, and some cases of vaginal and penile cancer, contributing to approximately 5% of cancers worldwide. The development of cancer is a complex, multi-step process characterized by dysregulation of signaling pathways and alterations in metabolic pathways. Extensive research has demonstrated that metabolic reprogramming plays a key role in the progression of various cancers, such as cervical, head and neck, bladder, and prostate cancers, providing the material and energy foundation for rapid proliferation and migration of cancer cells. Metabolic reprogramming of tumor cells allows for the rapid generation of ATP, aiding in meeting the high energy demands of HPV-related cancer cell proliferation. The interaction between Human Papillomavirus (HPV) and its associated cancers has become a recent focus of investigation. The impact of HPV on cellular metabolism has emerged as an emerging research topic. A significant body of research has shown that HPV influences relevant metabolic signaling pathways, leading to cellular metabolic alterations. Exploring the underlying mechanisms may facilitate the discovery of biomarkers for diagnosis and treatment of HPV-associated diseases. In this review, we introduced the molecular structure of HPV and its replication process, discussed the diseases associated with HPV infection, described the energy metabolism of normal cells, highlighted the metabolic features of tumor cells, and provided an overview of recent advances in potential therapeutic targets that act on cellular metabolism. We discussed the potential mechanisms underlying these changes. This article aims to elucidate the role of Human Papillomavirus (HPV) in reshaping cellular metabolism and the application of metabolic changes in the research of related diseases. Targeting cancer metabolism may serve as an effective strategy to support traditional cancer treatments, as metabolic reprogramming is crucial for malignant transformation in cancer.

In the past 5 years, a convergence of studies has resulted in a broad appreciation in the cancer research community that reprogramming of cellular metabolism may be more central to cancer than appreciated in the past 30 years. The re-emergence of cancer metabolism stems in part from discoveries that a number of common oncogenes and tumor suppressor genes more directly control cell metabolism than previously thought. In addition, a number of what would previously have been called “card-carrying” metabolic enzymes have been identified as human tumor suppressors or oncogenes, causally mutated in a variety of human cancers. This growing appreciation of the role of altered cell metabolism has led to further investigation into the rate-limiting proteins involved in different aspects of the unique metabolism of tumor cells. Targeting cancer metabolism with drugs requires a therapeutic window in which tumor cells, compared to normal tissues, have a greater dependence on specific metabolic enzymes. Themes that have emerged in the past decade of developing oncogene-targeted cancer therapeutics suggest that tumors with distinct oncogenic lesions are likely to require drugs that target distinct metabolic pathways. Ultimately, the hope is that detailed knowledge of oncogene and tumor suppressor gene functions and their effects on metabolism will lead to drug combinations that will be far more effective in treating cancers.