FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors

Fetal hemoglobin (HbF) improves the clinical severity of sickle cell disease (SCD), therefore, research to identify HbF-inducing agents for treatment purposes is desirable. The focus of our study is to investigate the ability of FK228 analogues to induce HbF using a novel KU812 dual-luciferase reporter system. Molecular modeling studies showed that the structure of twenty FK228 analogues with isosteric substitutions did not disturb the global structure of the molecule. Using the dual-luciferase system, a subgroup of FK228 analogues was shown to be inducers of HbF at nanomolar concentrations. To determine the physiological relevance of these compounds, studies in primary erythroid progenitors confirmed that JMA26 and JMA33 activated HbF synthesis at levels comparable to FK228 with low cellular toxicity. These data support our lead compounds as potential therapeutic agents for further development in the treatment of SCD

Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma.

Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue

Linking Metabolism With Dna Repair: Role Of Atp-Citrate Lyase

Maintaining genomic integrity and sustaining bioenergetics are both fundamental biological functions of normal proliferating cells. Crosstalk between metabolic and DNA repair pathways are poorly understood. Histone acetylation is a key factor in enabling recognition of DNA damage and in recruitment of DNA repair proteins to facilitate repair in a coordinated fashion. Acetyl-CoA modulations, in a nutrient sensitive manner, can influence global histone acetylation in proliferating cells. Given the importance of acetylation in the DNA damage response, we investigated a role for the metabolic regulation of histone acetylation following DNA damage. Herein, we report that nuclear ATP-citrate lyase (ACLY) is phosphorylated at S455, downstream of ATM and AKT, following DNA damage in a cell-cycle dependent manner. Functionally, ACLY promotes histone acetylation at double strand break sites (DSBs) to facilitate BRCA1 recruitment at the expense of 53BP1 to facilitate homologous recombination. ACLY catalytic activity, phosphorylation, and nuclear localization enhances BRCA1 focal accumulation at damage sites. Loss of ACLY promotes genomic instability and cell death following PARP inhibition. Coordinated spatial and temporal regulation of ACLY-dependent acetyl-CoA production mediates homologous recombination at the expense of non-homologous end-joining

Emerging Roles for Branched-Chain Amino Acid Metabolism in Cancer

© 2020 Elsevier Inc. Metabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers, with changes in branched-chain amino acid metabolism specifically affecting cancer cell state as well as systemic metabolism in individuals with malignancy. This review highlights key concepts surrounding the current understanding of branched-chain amino acid metabolism and its role in cancer

Transcriptional activation of macropinocytosis by the Hippo pathway following nutrient limitation

Cancer cells must adapt metabolism to thrive despite nutrient limitations in the tumor microenvironment. In this issue of Genes & Development, King and colleagues (pp. 1345-1358) report a role for transcriptional regulators of the Hippo pathway to facilitate protein scavenging and support proliferation under some nutrient-deprived conditions

Interactions with stromal cells promote a more oxidized cancer cell redox state in pancreatic tumors

Access to electron acceptors supports oxidized biomass synthesis and can be limiting for cancer cell proliferation, but how cancer cells overcome this limitation in tumors is incompletely understood. Nontransformed cells in tumors can help cancer cells overcome metabolic limitations, particularly in pancreatic cancer, where pancreatic stellate cells (PSCs) promote cancer cell proliferation and tumor growth. However, whether PSCs affect the redox state of cancer cells is not known. By taking advantage of the endogenous fluorescence properties of reduced nicotinamide adenine dinucleotide and oxidized flavin adenine dinucleotide cofactors we use optical imaging to assess the redox state of pancreatic cancer cells and PSCs and find that direct interactions between PSCs and cancer cells promote a more oxidized state in cancer cells. This suggests that metabolic interaction between cancer cells and PSCs is a mechanism to overcome the redox limitations of cell proliferation in pancreatic cancer.</jats:p

ATM Couples Replication Stress and Metabolic Reprogramming during Cellular Senescence

SummaryReplication stress induced by nucleotide deficiency plays an important role in cancer initiation. Replication stress in primary cells typically activates the cellular senescence tumor-suppression mechanism. Senescence bypass correlates with development of cancer, a disease characterized by metabolic reprogramming. However, the role of metabolic reprogramming in the cellular response to replication stress has been little explored. Here, we report that ataxia telangiectasia mutated (ATM) plays a central role in regulating the cellular response to replication stress by shifting cellular metabolism. ATM inactivation bypasses senescence induced by replication stress triggered by nucleotide deficiency. This was due to restoration of deoxyribonucleotide triphosphate (dNTP) levels through both upregulation of the pentose phosphate pathway via increased glucose-6-phosphate dehydrogenase (G6PD) activity and enhanced glucose and glutamine consumption. These phenotypes were mediated by a coordinated suppression of p53 and upregulation of c-MYC downstream of ATM inactivation. Our data indicate that ATM status couples replication stress and metabolic reprogramming during senescence

Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma

Funder: Jane Coffin Childs Memorial Fund for Medical Research; FundRef: http://dx.doi.org/10.13039/100001033Funder: Swedish Foundation for Strategic Research; FundRef: http://dx.doi.org/10.13039/501100001729Funder: Knut and Alice Wallenberg Foundation; FundRef: http://dx.doi.org/10.13039/501100004063Funder: Barbro Osher Pro Suecia Foundation; FundRef: http://dx.doi.org/10.13039/100008483Funder: Howard Hughes Medical Institute; FundRef: http://dx.doi.org/10.13039/100000011Funder: NIHR Cambridge BRCFunder: Lustgarten Foundation; FundRef: http://dx.doi.org/10.13039/100005979Funder: Stand Up To Cancer; FundRef: http://dx.doi.org/10.13039/100009730Funder: MIT Center for Precision Cancer MedicineFunder: Ludwig Center at MITFunder: Emerald FoundationTumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue

Increased Serine Synthesis Provides an Advantage for Tumors Arising in Tissues Where Serine Levels Are Limiting

Tumors exhibit altered metabolism compared to normal tissues. Many cancers upregulate expression of serine synthesis pathway enzymes, and some tumors exhibit copy-number gain of the gene encoding the first enzyme in the pathway, phosphoglycerate dehydrogenase (PHGDH). However, whether increased serine synthesis promotes tumor growth and how serine synthesis benefits tumors is controversial. Here, we demonstrate that increased PHGDH expression promotes tumor progression in mouse models of melanoma and breast cancer, human tumor types that exhibit PHGDH copy-number gain. We measure circulating serine levels and find that PHGDH expression is necessary to support cell proliferation at lower physiological serine concentrations. Increased dietary serine or high PHGDH expression is sufficient to increase intracellular serine levels and support faster tumor growth. Together, these data suggest that physiological serine availability restrains tumor growth and argue that tumors arising in serine-limited environments acquire a fitness advantage by upregulating serine synthesis pathway enzymes. Nutrient availability can constrain tumor growth. Sullivan et al. demonstrate that in some cancers, physiological levels of the amino acid serine are insufficient to support maximal tumor growth and that melanoma and breast tumors derive a growth advantage by upregulating serine biosynthesis.National Science Foundation (Grant DGE-1122374)National Science Foundation (Grant T32-GM007287)National Science Foundation (Grant F32CA213810)National Science Foundation (Grant R21CA198028)National Science Foundation (Grant R01CA168653