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Many cancer cells share with yeast a preference for fermentation over respiration, which is associated with overactive glucose uptake and breakdown, a phenomenon called the Warburg effect in cancer cells. The yeast tps1D mutant shows even more pronounced hyperactive glucose uptake and phosphorylation causing glycolysis to stall at GAPDH, initiation of apoptosis through overactivation of Ras and absence of growth on glucose. The goal of the present work was to use the yeast tps1D strain to screen for novel compounds that would preferentially inhibit overactive glucose influx into glycolysis, while maintaining basal glucose catabolism. This is based on the assumption that the overactive glucose catabolism of the tps1D strain might have a similar molecular cause as the Warburg effect in cancer cells. We have isolated Warbicin® A as a compound restoring growth on glucose of the yeast tps1D mutant, showed that it inhibits the proliferation of cancer cells and isolated structural analogs by screening directly for cancer cell inhibition. The Warbicin® compounds are the first drugs that inhibit glucose uptake by both yeast Hxt and mammalian GLUT carriers. Specific concentrations did not evoke any major toxicity in mice but increase the amount of adipose tissue likely due to reduced systemic glucose uptake. Surprisingly, Warbicin® A inhibition of yeast sugar uptake depends on sugar phosphorylation, suggesting transport-associated phosphorylation as a target. In vivo and in vitro evidence confirms physical interaction between yeast Hxt7 and hexokinase. We suggest that reversible transport-associated phosphorylation by hexokinase controls the rate of glucose uptake through hydrolysis of the inhibitory ATP molecule in the cytosolic domain of glucose carriers and that in yeast tps1D cells and cancer cells reversibility is compromised, causing constitutively hyperactive glucose uptake and phosphorylation. Based on their chemical structure and properties, we suggest that Warbicin® compounds replace the inhibitory ATP molecule in the cytosolic domain of the glucose carriers, preventing hexokinase to cause hyperactive glucose uptake and catabolism. [ABSTRACT FROM AUTHOR]

If you are a scientist and you only know one thing about tumor metabolism, it's likely the Warburg effect. But who was Otto Warburg, and how did his discoveries regarding the metabolism of tumors shape our current thinking about the metabolic needs of cancer cells? Sarah-Maria Fendt highlights the history of the Warburg effect and how these findings have advanced our understanding of cancer metabolism. [ABSTRACT FROM AUTHOR]

Glioblastoma is a highly lethal grade of astrocytoma with very low median survival. Despite extensive efforts, there is still a lack of alternatives that might improve these prospects. We uncovered that the chemotherapeutic agent temozolomide impinges on fatty acid synthesis and desaturation in newly diagnosed glioblastoma. This response is, however, blunted in recurring glioblastoma from the same patient. Further, we describe that disrupting cellular fatty acid homeostasis in favor of accumulation of saturated fatty acids such as palmitate synergizes with temozolomide treatment. Pharmacological inhibition of SCD and/or FADS2 allows palmitate accumulation and thus greatly augments temozolomide efficacy. This effect was independent of common GBM prognostic factors and was effective against cancer cells from recurring glioblastoma. In summary, we provide evidence that intracellular accumulation of saturated fatty acids in conjunction with temozolomide based chemotherapy induces death in glioblastoma cells derived from patients. [ABSTRACT FROM AUTHOR]

Metastasis formation is the leading cause of death in cancer patients. Thus, understanding and targeting this process is an unmet need. Crucial steps during the establishment of metastases include the (pre)metastatic niche formation. This process relies on the interaction of the primary tumor with the environment of distant organs (premetastatic niche) and the interaction of cancer cells with their environment when arriving in a distant organ (metastatic niche). Here, we summarize the current knowledge on the interactions in the tumor environment that result in (pre)metastatic niche formation, specifically in the context of tumor secreted factors, extracellular matrix, immune as well as stromal cells, and nutrient availability. We further highlight strategies to disrupt these interactions as therapeutic interventions against metastases. [ABSTRACT FROM AUTHOR]

Metabolism is tied into complex interactions with cell intrinsic and extrinsic processes that go beyond the conversion of nutrients into energy and biomass. Indeed, metabolism is a central cellular hub that interconnects and influences the microenvironment, the cellular phenotype, cell signaling, and the (epi)genetic landscape. While these interactions evolved to support survival and function of normal cells, they are hijacked by cancer cells to enable cancer maintenance and progression. Thus, a mechanistic and functional understanding of complex metabolic interactions provides a basis for the discovery of novel metabolic vulnerabilities in cancer. In this review, we will summarize and provide context for the to-date discovered complex metabolic interactions by discussing how the microenvironment as well as the cellular phenotype define cancer metabolism, and how metabolism shapes the epigenetic state of cancer cells. Many of the studies investigating the crosstalk of metabolism with cell intrinsic and extrinsic processes have used integrative data analysis approaches at the interface between computational and experimental cancer research, and we will highlight those throughout the review. In conclusion, identifying and understanding complex metabolic interactions is a basis for deciphering novel metabolic vulnerabilities of cancer cells. WIREs Syst Biol Med 2018, 10:e1397. doi: 10.1002/wsbm.1397 This article is categorized under: Biological Mechanisms > Metabolism, Physiology > Mammalian Physiology in Health and Disease [ABSTRACT FROM AUTHOR]

Cells that have undergone an oncogenic transformation have an altered metabolism compared to the cells they originate from (1). This observation led to the addition of "a deregulated metabolism" to the hallmarks of cancer (2). Accordingly, it has been extensively demonstrated that many of the observed alterations in the metabolism of cancer cells are important for their proliferation (1, 3, 4). However, a metabolic alteration that is important for cancer cell proliferation is not automatically a good target for treatment, as treatments also have to be selective toward cancer cells. Since almost all of the cancer-induced metabolic changes are not caused by gain of function mutations in specific enzymes, metabolism-based drug have to be developed against the naturally occurring enzymes. Thus, the valid question arises whether there is a therapeutic window for targeting the deregulated metabolism of cancer cells. In the following, I would like to describe the challenges and advocate the opportunities for metabolic drug targets in cancer treatment. In the first section, I will address the question whether there is in general a therapeutic window for metabolism-based cancer treatment, while in the second section, I will discuss new concepts that can refine metabolism-based anticancer strategies. [ABSTRACT FROM AUTHOR]

Cancer cells reprogram their metabolism to promote growth and proliferation. The genetic evidence pointing to the importance of the amino acid serine in tumorigenesis is striking. The gene encoding the enzyme 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the first committed step of serine biosynthesis, is overexpressed in tumors and cancer cell lines via focal amplification and nuclear factor erythroid-2-related factor 2 (NRF2)-mediated up-regulation. PHGDH-overexpressing cells are exquisitely sensitive to genetic ablation of the pathway. Here, we report the discovery of a selective small molecule inhibitor of PHGDH, CBR-5884, identified by screening a library of 800,000 drug-like compounds. CBR-5884 inhibited de novo serine synthesis in cancer cells and was selectively toxic to cancer cell lines with high serine biosynthetic activity. Biochemical characterization of the inhibitor revealed that it was a noncompetitive inhibitor that showed a time-dependent onset of inhibition and disrupted the oligomerization state of PHGDH. The identification of a small molecule inhibitor of PHGDH not only enables thorough preclinical evaluation of PHGDH as a target in cancers, but also provides a tool with which to study serine metabolism. [ABSTRACT FROM AUTHOR]

The metabolic engineer's toolbox, comprising stable isotope tracers, flux estimation and analysis, pathway identification, and pathway kinetics and regulation, among other techniques, has long been used to elucidate and quantify pathways primarily in the context of engineering microbes for producing small molecules of interest. Recently, these tools are increasingly finding use in cancer biology due to their unparalleled capacity for quantifying intracellular metabolism of mammalian cells. Here, we review basic concepts that are used to derive useful insights about the metabolism of tumor cells, along with a number of illustrative examples highlighting the fundamental contributions of these methods to elucidating cancer cell metabolism. This area presents unique opportunities for metabolic engineering to expand its portfolio of applications into the realm of cancer biology and help develop new cancer therapies based on a new class of metabolically derived targets. © 2012 American Institute of Chemical Engineers Biotechnol. Prog., 2012 [ABSTRACT FROM AUTHOR]

Recent evidence suggests that type II diabetes is associated with increased risk and/or aggressive behavior of several cancers, including those arising from the colon. Concerns have been raised that endogenous hyperinsulinemia and/or exogenous insulin and insulin analogs might stimulate proliferation of neoplastic cells. However, the mechanisms underlying possible growth-promoting effects of insulin and insulin analogs in cancer cells in vivo, such as changes in gene expression, are incompletely described. We observed that administration of the insulin analog X10 significantly increased tumor growth and proliferation in a murine colon cancer model (MC38 cell allografts). Insulin and X10 altered gene expression in MC38 tumors in a similar fashion, but X10 was more potent in terms of the number of genes influenced and the magnitude of changes in gene expression. Many of the affected genes were annotated to metabolism, nutrient uptake, and protein synthesis. Strikingly, expression of genes encoding enzymes in the serine synthesis pathway, recently shown to be critical for neoplastic proliferation, was increased following treatment with insulin and X10. Using stable isotopic tracers and mass spectrometry, we confirmed that insulin and X10 increased glucose contribution to serine synthesis in MC38 cells. The data demonstrate that the tumor growth-promoting effects of insulin and X10 are associated with changes in expression of genes involved in cellular energy metabolism and reveal previously unrecognized effects of insulin and X10 on serine synthesis. [ABSTRACT FROM AUTHOR]

Most cancer patients die due to metastasis formation. Therefore, understanding, preventing, and treating metastatic cancers is an unmet need. Recent research indicates that cancer cells that undergo metastasis formation have a distinct metabolism that can be targeted. Here, I would like to discuss potential opportunities in exploiting the metabolic vulnerabilities of metastasizing cancer cells. [ABSTRACT FROM AUTHOR]

Metastasis to distant organs is a predictor of poor prognosis. Therefore, it is of paramount importance to understand the mechanisms that impinge on the different steps of the metastatic cascade. Recent work has revealed that particular metabolic pathways are rewired in cancer cells to support their transition through the metastatic cascade, resulting in the formation of secondary tumors in distant organs. Indeed, metabolic rewiring induces signaling pathways during initial cancer invasion, circulating cancer cells depend on enhanced antioxidant defenses, and cancer cells colonizing a distant organ require increased ATP production. Moreover, the local environment of the metastatic niche dictates the metabolic pathways secondary tumors rely on. Here we describe mechanisms of metabolic rewiring associated with distinct steps of metastasis formation. [ABSTRACT FROM AUTHOR]

Cancer cells frequently lack nutrients like glucose, due to insufficient vascular networks. Mitochondrial phosphoenolpyruvate carboxykinase, PCK2, has recently been found to mediate partial gluconeogenesis and hence anabolic metabolism in glucose starved cancer cells. Here we show that PCK2 acts as a regulator of mitochondrial respiration and maintains the redox balance in nutrient-deprived human lung cancer cells. PCK2 silencing increased the abundance and interconversion of tricarboxylic acid (TCA) cycle intermediates, augmented mitochondrial respiration and enhanced glutathione oxidation under glucose and serum starvation, in a PCK2 re-expression reversible manner. Moreover, enhancing the TCA cycle by PCK2 inhibition severely reduced colony formation of lung cancer cells under starvation. As a conclusion, PCK2 contributes to maintaining a reduced glutathione pool in starved cancer cells besides mediating the biosynthesis of gluconeogenic/glycolytic intermediates. The study sheds light on adaptive responses in cancer cells to nutrient deprivation and shows that PCK2 confers protection against respiration-induced oxidative stress. [Display omitted] • The gluconeogenesis enzyme PCK2 removes glutamine-derived TCA cycle intermediates in starved lung cancer cells. • Thereby, PCK2 regulates mitochondrial respiration, besides fueling gluconeogenesis downstream pathways. • By reducing respiration, PCK2 contributes to maintaining the glutathione redox balance. • Consequently, PCK2 enhances the colony forming capability of lung cancer cells. [ABSTRACT FROM AUTHOR]

Tumors undergo metabolic transformations to sustain uncontrolled proliferation, avoid cell death, and seed in secondary organs. An increased focus on cancer lipid metabolism has unveiled a number of mechanisms that promote tumor growth and survival, many of which are independent of classical cellular bioenergetics. These mechanisms include modulation of ferroptotic-mediated cell death, support during tumor metastasis, and interactions with the cells of the tumor microenvironment. As such, targeting lipid metabolism for anti-cancer therapies is attractive, with recent work on small-molecule inhibitors identifying compounds to target lipid metabolism. Here, we discuss these topics and identify open questions. Broadfield et al. present a review discussing the metabolic transformations undergone by cancer cells. They discuss modulation of ferroptotic-mediated cell death, tumor metastasis, and interactions with the cells of the microenvironment, as well as identification of compounds to target lipid metabolism. [ABSTRACT FROM AUTHOR]