Search

In this issue of Molecular Cell, show that the switch from oxidative phosphorylation to glycolysis in cancer cells is regulated by tyrosine phosphorylation of PDHK1. [ABSTRACT FROM AUTHOR]

Summary: The ability of activated Ras to induce growth arrest of human ovarian surface epithelial (HOSE) cells via induction of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 has been used to screen for Ras pathway signaling components using a library of RNA interference (RNAi) vectors targeting the kinome. Two known Ras-regulated kinases were identified, phosphoinositide 3-kinase p110α and ribosomal protein S6 kinase p70S6K1, plus the MAP kinase kinase kinase kinase MINK, which had not previously been implicated in Ras signaling. MINK is activated after Ras induction via a mechanism involving reactive oxygen species and mediates stimulation of the stress-activated protein kinase p38 MAPK downstream of the Raf/ERK pathway. p38 MAPK activation is essential for Ras-induced p21WAF1/CIP1 upregulation and cell cycle arrest. MINK is thus a distal target of Ras signaling in the induction of a growth-arrested, senescent-like phenotype that may act to oppose oncogenic transformation in HOSE cells. [Copyright &y& Elsevier]

Metabolic rewiring is essential for cancer onset and progression. We previously showed that one-carbon metabolism-dependent formate production often exceeds the anabolic demand of cancer cells, resulting in formate overflow. Furthermore, we showed that increased extracellular formate concentrations promote the in vitro invasiveness of glioblastoma cells. Here, we substantiate these initial observations with ex vivo and in vivo experiments. We also show that exposure to exogeneous formate can prime cancer cells toward a pro-invasive phenotype leading to increased metastasis formation in vivo. Our results suggest that the increased local formate concentration within the tumor microenvironment can be one factor to promote metastases. Additionally, we describe a mechanistic interplay between formate-dependent increased invasiveness and adaptations of lipid metabolism and matrix metalloproteinase activity. Our findings consolidate the role of formate as pro-invasive metabolite and warrant further research to better understand the interplay between formate and lipid metabolism., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cholesterol is essential for the ability of cytotoxic T cells to eliminate cancer cells. In this issue of Cancer Cell, Yan et al. reveal how intra-tumoral cholesterol deficiency contributes to T cell exhaustion by inhibiting mTORC1 signaling. Moreover, they demonstrate that increasing cholesterol levels in chimeric antigen receptor (CAR)-T cells by blocking liver X receptor (LXR) leads to improved anti-tumor function., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

New findings by Altea-Manzano et al. demonstrate that primary breast tumours or a high-fat diet induce palmitate secretion by alveolar type 2 (AT2) cells to prepare a premetastatic niche that promotes lung metastasis. Palmitate is utilised by cancer cells via carnitine palmitoyltransferase 1a (CPT1a) and lysine acetyltransferase 2a (KAT2a) to acetylate nuclear factor-κB (NF-κB)/p65. Blocking these enzymes reduced metastasis formation in both lean and high-fat diet mice., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Many metabolic pathways, including lipid metabolism, are rewired in tumors to support energy and biomass production and to allow adaptation to stressful environments. Neuroblastoma is the second deadliest solid tumor in children. Genetic aberrations, as the amplification of the MYCN -oncogene, correlate strongly with disease progression. Yet, there are only a few molecular targets successfully exploited in the clinic. Here we show that inhibition of fatty acid synthesis led to increased neural differentiation and reduced tumor burden in neuroblastoma xenograft experiments independently of MYCN -status. This was accompanied by reduced levels of the MYCN or c-MYC oncoproteins and activation of ERK signaling. Importantly, the expression levels of genes involved in de novo fatty acid synthesis showed prognostic value for neuroblastoma patients. Our findings demonstrate that inhibition of de novo fatty acid synthesis is a promising pharmacological intervention strategy for the treatment of neuroblastoma independently of MYCN -status., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Cancer cells display an increased plasticity in their lipid metabolism, which includes the conversion of palmitate to sapienate via the enzyme fatty acid desaturase 2 (FADS2). We find that FADS2 expression correlates with mammalian target of rapamycin (mTOR) signaling and sterol regulatory element-binding protein 1 (SREBP-1) activity across multiple cancer types and is prognostic in some cancer types. Accordingly, activating mTOR signaling by deleting tuberous sclerosis complex 2 (Tsc2) or overexpression of SREBP-1/2 is sufficient to increase FADS2 mRNA expression and sapienate metabolism in mouse embryonic fibroblasts (MEFs) and U87 glioblastoma cells, respectively. Conversely, inhibiting mTOR signaling decreases FADS2 expression and sapienate biosynthesis in MEFs with Tsc2 deletion, HUH7 hepatocellular carcinoma cells, and orthotopic HUH7 liver xenografts. In conclusion, we show that mTOR signaling and SREBP activity are sufficient to activate sapienate metabolism by increasing FADS2 expression. Consequently, targeting mTOR signaling can reduce sapienate metabolism in vivo., Competing Interests: Declaration of Interests S.-M.F. has received funding from Bayer, Merck, and Black Belt Therapeutics and has consulted for Funds+., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Altered lipid metabolism is among the most prominent metabolic alterations in cancer. Enhanced synthesis or uptake of lipids contributes to rapid cancer cell growth and tumor formation. Lipids are a highly complex group of biomolecules that not only constitute the structural basis of biological membranes but also function as signaling molecules and an energy source. Here, we summarize recent evidence implicating altered lipid metabolism in different aspects of the cancer phenotype and discuss potential strategies by which targeting lipid metabolism could provide a therapeutic window for cancer treatment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Obesity is a leading contributing factor to cancer development worldwide. Epidemiological evidence suggests that diet affects cancer risk and also substantially alters therapeutic outcome. Therefore, studying the impact of diet in the development and treatment of cancer should be a clinical priority. In this Review, we set out the evidence supporting the role of lipid metabolism in shaping the tumor microenvironment (TME) and cancer cell phenotype. We will discuss how dietary lipids can impact phenotype thereby affecting disease trajectory and treatment response. Finally, we will posit potential strategies on how this knowledge can be exploited to increase treatment efficacy and patient survival., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Lipid metabolism is frequently perturbed in cancers, but the underlying mechanism is unclear. We present comprehensive evidence that oncogene MYC, in collaboration with transcription factor sterol-regulated element-binding protein (SREBP1), regulates lipogenesis to promote tumorigenesis. We used human and mouse tumor-derived cell lines, tumor xenografts, and four conditional transgenic mouse models of MYC-induced tumors to show that MYC regulates lipogenesis genes, enzymes, and metabolites. We found that MYC induces SREBP1, and they collaborate to activate fatty acid (FA) synthesis and drive FA chain elongation from glucose and glutamine. Further, by employing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we observed in vivo lipidomic changes upon MYC induction across different cancers, for example, a global increase in glycerophosphoglycerols. After inhibition of FA synthesis, tumorigenesis was blocked, and tumors regressed in both xenograft and primary transgenic mouse models, revealing the vulnerability of MYC-induced tumors to the inhibition of lipogenesis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Mutations are the basis of the clonal evolution of most cancers. Nevertheless, a systematic analysis of whether mutations are selected in cancer because they lead to the deregulation of specific biological processes independent of the type of cancer is still lacking. In this study, we correlated the genome and transcriptome of 1,082 tumors. We found that nine commonly mutated genes correlated with substantial changes in gene expression, which primarily converged on metabolism. Further network analyses circumscribed the convergence to a network of reactions, termed AraX, that involves the glutathione- and oxygen-mediated metabolism of arachidonic acid and xenobiotics. In an independent cohort of 4,462 samples, all nine mutated genes were consistently correlated with the deregulation of AraX. Among all of the metabolic pathways, AraX deregulation represented the strongest predictor of patient survival. These findings suggest that oncogenic mutations drive a selection process that converges on the deregulation of the AraX network., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

The "Rosies" of Cell Metabolism are back for the third part of the "Women in Metabolism" 2015 series. We are closing our anniversary celebrations with 14 inspiring and engaging new stories from women scientists in the metabolism field. A round of applause to all who contributed and supported this project!, (Copyright © 2015 Elsevier Inc. All rights reserved.)

A functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

An in vivo model of antiangiogenic therapy allowed us to identify genes upregulated by bevacizumab treatment, including Fatty Acid Binding Protein 3 (FABP3) and FABP7, both of which are involved in fatty acid uptake. In vitro, both were induced by hypoxia in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. There was a significant lipid droplet (LD) accumulation in hypoxia that was time and O2 concentration dependent. Knockdown of endogenous expression of FABP3, FABP7, or Adipophilin (an essential LD structural component) significantly impaired LD formation under hypoxia. We showed that LD accumulation is due to FABP3/7-dependent fatty acid uptake while de novo fatty acid synthesis is repressed in hypoxia. We also showed that ATP production occurs via β-oxidation or glycogen degradation in a cell-type-dependent manner in hypoxia-reoxygenation. Finally, inhibition of lipid storage reduced protection against reactive oxygen species toxicity, decreased the survival of cells subjected to hypoxia-reoxygenation in vitro, and strongly impaired tumorigenesis in vivo., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Tumors display distinct metabolic programs, and altered lipid metabolism is emerging as an important process in cancer. In this issue, Yue et al. (2014) report that aberrant cholesteryl ester accumulation is found in advanced prostate cancers with PTEN loss and PI3K/AKT activation. Importantly, inhibition of cholesterol esterification impaired cancer aggressiveness., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Cancer cells often have characteristic changes in metabolism. Cellular proliferation, a common feature of all cancers, requires fatty acids for synthesis of membranes and signaling molecules. Here, we provide a view of cancer cell metabolism from a lipid perspective, and we summarize evidence that limiting fatty acid availability can control cancer cell proliferation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Glycogen metabolism operates as an alternative energy source, enabling cell growth under conditions of metabolic stress. Favaro et al. (2012) now demonstrate that in hypoxic cancer cells, depletion of liver glycogen phosphorylase causes glycogen accumulation, leading to oxidative stress, induction of senescence, and impaired tumor growth in vivo., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Cell growth (accumulation of mass) needs to be coordinated with metabolic processes that are required for the synthesis of macromolecules. The PI3-kinase/Akt signaling pathway induces cell growth via activation of complex 1 of the target of rapamycin (TORC1). Here we show that Akt-dependent lipogenesis requires mTORC1 activity. Furthermore, nuclear accumulation of the mature form of the sterol responsive element binding protein (SREBP1) and expression of SREBP target genes was blocked by the mTORC1 inhibitor rapamycin. We also show that silencing of SREBP blocks Akt-dependent lipogenesis and attenuates the increase in cell size in response to Akt activation in vitro. Silencing of dSREBP in flies caused a reduction in cell and organ size and blocked the induction of cell growth by dPI3K. Our results suggest that the PI3K/Akt/TOR pathway regulates protein and lipid biosynthesis in an orchestrated manner and that both processes are required for cell growth.