bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2024–12–08
fourteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. CX43-mediated mitochondrial transfer maintains stemness of KG-1a leukemia stem cells through metabolic remodeling.
  2. TIFAB Modulates Metabolic Pathways in KMT2A::MLLT3-Induced AML Through HNF4A.
  3. Coordination of cytochrome bc1 complex assembly at MICOS.
  4. Species differences in glycerol-3-phosphate metabolism reveals trade-offs between metabolic adaptations and cell proliferation.
  5. Unraveling bidirectional evolution of unstable mitochondrial DNA mutations in hepatocellular carcinoma at single-cell resolution.
  6. p53 induces circFRMD4A to suppress cancer development through glycolytic reprogramming and cuproptosis.
  7. Mitochondrial Metabolism as a Potential Novel Therapeutic Target for Lung Adenocarcinoma.
  8. Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells.
  9. Inside-out submitochondrial particles affect the mitochondrial permeability transition pore opening under conditions of mitochondrial dysfunction.
  10. Proton Sensing GPCR's: The missing link to Warburg's Oncogenic Legacy?
  11. The dynamics of hematopoiesis over the human lifespan.
  12. Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer.
  13. Role of ATP citrate lyase and its complementary partner on fatty acid synthesis in gastric cancer.
  14. Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma.
  1. Stem Cell Res Ther. 2024 Dec 02. 15(1): 460
    CX43-mediated mitochondrial transfer maintains stemness of KG-1a leukemia stem cells through metabolic remodeling.
    Huihui Fu, Xiaoqing Xie, Liuyue Zhai, Yi Liu, Yifeng Tang, Sanxiu He, Jun Li, Qing Xiao, Guofa Xu, Zailin Yang, Xiaomei Zhang, Yao Liu.
       BACKGROUND: Acute myeloid leukemia (AML) is characterized by abundant immature myeloid cells, relapse and refractory due to leukemia stem cells (LSCs). Bone marrow mesenchymal stem/ stromal cells (BMSCs) supported LSCs survival, meanwhile, chemotherapy improved connexin43 (CX43) expression. CX43, as the most intercellular gap junction, facilitated transmit mitochondria from BMSCs into AML. We hypothesized that increased mitochondria transferred from BMSCs supported metabolic remodeling in LSCs to sustain their stemness.
    METHODS: Primary BMSCs from AML patients were isolated. CX43-BMSCs, overexpressing CX43, were cocultured with KG-1a cells. Fluorescence and confocal microscopy observed mitochondrial transfer. Flow cytometry, EdU assay, and clonogenicity evaluated cell cycle, proliferation, and clonogenic potential. Xenograft mouse models were used to evaluate the tumorigenicity of KG-1a in vivo. Seahorse, RNA-seq, and LC-MS assessed mitochondrial function, transcriptomes, and metabolites post-coculture.
    RESULTS: CX43-BMSCs promoted unidirectional mitochondrial transfer, enhancing KG-1a adhesion and proliferation to maintain LSCs stemness in vitro and vivo. RNA-seq revealed coculture with CX43-BMSCs upregulated genes related to adhesion, proliferation, and migration in KG-1a cells. Elevated CX43 expression strengthened BMSCs-KG-1a interaction, facilitating mitochondrial transfer and nucleoside metabolism, fueling KG-1a cells. This enhanced mitochondrial energy metabolism, promoting metabolic reprogramming and clonogenicity.
    CONCLUSION: CX43-mediated mitochondrial transfer from BMSCs to KG-1a enhances LSCs adhesion, proliferation, clonogenicity, and metabolic reprogramming. CX43 emerges as a potential therapeutic target for AML by sustaining LSCs stemness through metabolic remodeling.
    Keywords:  Adhesion; Bone marrow microenvironment; Connexin; Leukemia stem cells; Metabolic remodeling; Mitochondrial transfer
    DOI:  https://doi.org/10.1186/s13287-024-04079-3
  2. Blood Adv. 2024 Dec 03. pii: bloodadvances.2024013446. [Epub ahead of print]
    TIFAB Modulates Metabolic Pathways in KMT2A::MLLT3-Induced AML Through HNF4A.
    Yang Wang, Yan Xiu, Qianze Dong, Jinming Zhao, Kelao Neumbo, Masaru Miyagi, Nicholas Borcherding, Lin Fu, Havana Ray De Celis, Nicolas Giuseppe Pintozzi, Daniel T Starczynowski, Chen Zhao.
      TRAF-interacting protein with forkhead-associated domain B (TIFAB), an inhibitor of NF-kB signaling, plays critical roles in hematopoiesis, myelodysplastic neoplasms, and leukemia. We previously demonstrated that Tifab enhances KMT2A::MLLT3-driven acute myeloid leukemia (AML) by either upregulating Hoxa9 or through ubiquitin-specific peptidase 15 (USP15)-mediated downregulation of p53 signaling. In this study, we show that Tifab deletion in KMT2A::MLLT3-induced AML impairs leukemia stem/progenitor cell (LSPC) engraftment, glucose uptake, and mitochondrial function. Gene Set Enrichment Analysis reveals that Tifab deletion downregulates MYC, HOXA9/MEIS1, mTORC1 signaling, and genes involved in glycolysis and oxidative phosphorylation (OXPHOS). By comparing genes upregulated in TIFAB-overexpressing LSPCs with those downregulated upon Tifab deletion, we identify hepatocyte nuclear factor 4alpha (Hnf4a) as a key TIFAB target, regulated through the inhibition of NF-kB component RelB, which suppresses Hnf4a in leukemia cells. HNF4A, a nuclear receptor involved in organ development, metabolism, and tumorigenesis, rescues the metabolic defects caused by Tifab deletion and enhances leukemia cell engraftment. Conversely, Hnf4a knockdown attenuates TIFAB-mediated enhancement of LSPC function. These findings highlight the critical role of the TIFAB-HNF4A axis in KMT2A::MLLT3-induced AML and uncover a novel regulator in leukemia biology.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013446
  3. EMBO Rep. 2024 Dec 02.
    Coordination of cytochrome bc1 complex assembly at MICOS.
    Ralf M Zerbes, Lilia Colina-Tenorio, Maria Bohnert, Karina von der Malsburg, Christian D Peikert, Carola S Mehnert, Inge Perschil, Rhena F U Klar, Rinse de Boer, Anita Kram, Ida van der Klei, Silke Oeljeklaus, Bettina Warscheid, Heike Rampelt, Martin van der Laan.
      The boundary and cristae domains of the mitochondrial inner membrane are connected by crista junctions. Most cristae membrane proteins are nuclear-encoded and inserted by the mitochondrial protein import machinery into the inner boundary membrane. Thus, they must overcome the diffusion barrier imposed by crista junctions to reach their final location. Here, we show that respiratory chain complexes and assembly intermediates are physically connected to the mitochondrial contact site and cristae organizing system (MICOS) that is essential for the formation and stability of crista junctions. We identify the inner membrane protein Mar26 (Fmp10) as a determinant in the biogenesis of the cytochrome bc1 complex (complex III). Mar26 couples a Rieske Fe/S protein-containing assembly intermediate to MICOS. Our data indicate that Mar26 maintains an assembly-competent Rip1 pool at crista junctions where complex III maturation likely occurs. MICOS facilitates efficient Rip1 assembly by recruiting complex III assembly intermediates to crista junctions. We propose that MICOS, via interaction with assembly factors such as Mar26, contributes to the spatial and temporal coordination of respiratory chain biogenesis.
    Keywords:   bc 1 Complex; Cristae; MICOS; Mitochondria; Respiratory Chain
    DOI:  https://doi.org/10.1038/s44319-024-00336-x
  4. Biochim Biophys Acta Bioenerg. 2024 Dec 02. pii: S0005-2728(24)00500-0. [Epub ahead of print] 149530
    Species differences in glycerol-3-phosphate metabolism reveals trade-offs between metabolic adaptations and cell proliferation.
    Kateryna Gaertner, Mügen Terzioglu, Craig Michell, Riikka Tapanainen, Jaakko Pohjoismäki, Eric Dufour, Sina Saari.
      The temperate climate-adapted brown hare (Lepus europaeus) and the cold-adapted mountain hare (Lepus timidus) are closely related and interfertile species. However, their skin fibroblasts display distinct gene expression profiles related to fundamental cellular processes. This indicates important metabolic divergence between the two species. Through targeted metabolomics and metabolite tracing, we identified species-specific variations in glycerol 3-phosphate (G3P) metabolism. G3P is a key metabolite of the G3P shuttle, which transfers reducing equivalents from cytosolic NADH to the mitochondrial electron transport chain (ETC), consequently regulating glycolysis, lipid metabolism, and mitochondrial bioenergetics. Alterations in G3P metabolism have been implicated in multiple human pathologies including cancer and diabetes. We observed that mountain hare mitochondria exhibit elevated G3P shuttle activity, alongside increased membrane potential and decreased mitochondrial temperature. Silencing mitochondrial G3P dehydrogenase (GPD2), which couples the conversion of G3P to the ETC, uncovered its species-specific role in controlling mitochondrial membrane potential and highlighted its involvement in skin fibroblast thermogenesis. Unexpectedly, GPD2 silencing enhanced wound healing and cell proliferation rates in a species-specific manner. Our study underscores the pivotal role of the G3P shuttle in mediating physiological, bioenergetic, and metabolic divergence between these hare species.
    Keywords:  Glycerol-3-phosphate; Hares; Metabolism; Mitochondria; Mitochondrial membrane potential; Thermogenesis; Wound healing
    DOI:  https://doi.org/10.1016/j.bbabio.2024.149530
  5. Hepatology. 2024 Oct 11.
    Unraveling bidirectional evolution of unstable mitochondrial DNA mutations in hepatocellular carcinoma at single-cell resolution.
    Kaixiang Zhou, Zhenni Wang, Wenjie Guo, Fanfan Xie, Qing Yuan, Shanshan Guo, Huanqin Zhang, Yang Liu, Xiwen Gu, Wenjie Song, Xu Guo, Jinliang Xing.
       BACKGROUND AND AIMS: Somatic mutations in mitochondrial DNA (mtDNA) are abundant in HCC and directly affect metabolic homeostasis and tumor progression. The mixed population of mutant and wild-type mtDNA alleles within a cell, termed heteroplasmy, can vary from cell-to-cell and orchestrate tumorigenesis. However, the systematic evolutionary dynamics of somatic mtDNA mutations in HCC tissues remain to be delineated at single-cell resolution.
    APPROACH AND RESULTS: We established the single-cell capture-based mtDNA sequencing approach for accurately detecting somatic mtDNA mutations at single-cell resolution. Based on single-cell capture-based mtDNA sequencing, the single-cell somatic mtDNA mutational landscape, intratumor heterogeneity (ITH), and spatiotemporal clonal evolution were systematically investigated in 1641 single cells from 11 patients with HCC and 528 single cells from 2 patient-derived xenografts mouse models. Our data revealed the presence of 2 distinct categories of mtDNA mutation at single-cell resolution, including stable mutations exhibiting similar heteroplasmy levels and unstable mutations exhibiting remarkable cell-to-cell variability of heteroplasmy levels. Furthermore, the proportion of unstable mtDNA mutations was positively associated with the ITH of patients with HCC, with high ITH reflecting the proliferative and aggressive clinicopathological features of HCC cells. In addition, reconstruction of the evolutionary history classified HCC evolution patterns as linear or branched. Notably, spatiotemporal lineage tracing in patient-derived xenograft mouse models and multifocal lesions revealed bidirectional evolution of unstable mtDNA mutations during HCC progression.
    CONCLUSIONS: Our study unravels the landscape of single-cell somatic mtDNA mutations in HCC tissues and reveals the bidirectional evolution of unstable mtDNA mutations, with potential implications for HCC stratification and therapeutic intervention.
    DOI:  https://doi.org/10.1097/HEP.0000000000001113
  6. Mol Cell. 2024 Nov 27. pii: S1097-2765(24)00918-3. [Epub ahead of print]
    p53 induces circFRMD4A to suppress cancer development through glycolytic reprogramming and cuproptosis.
    Quan Liao, Jun Deng, Jing Tong, Yu Gan, Weiwei Hong, Hanzhi Dong, Mingming Cao, Chen Xiong, Yajie Chen, Bangxiang Xie, Fu-Ying Yang, Aikede Alifu, Guang-Biao Zhou, Shenglin Huang, Jianping Xiong, Qian Hao, Xiang Zhou.
      Cuproptosis is a type of copper-induced cell death that mainly impacts cells relying on mitochondrial metabolism. Although p53 regulates glycolytic metabolism, its role in cuproptosis remains unclear. Here, we report that the circular RNA, circFRMD4A, is crucial for p53-mediated metabolic reprogramming and cuproptosis. CircFRMD4A originates from the transcript of FRMD4A, which is transcriptionally activated by p53, and the formation of circFRMD4A is facilitated by the RNA-binding protein EWSR1. CircFRMD4A functions as a tumor suppressor and enhances the sensitivity of cancer cells to elesclomol-induced cuproptosis. Mechanistic analysis reveals that circFRMD4A interacts with and inactivates the pyruvate kinase PKM2, leading to a decrease in lactate production and a redirection of glycolytic flux toward the tricarboxylic acid cycle. Finally, p53 agonists and elesclomol coordinately suppress the growth of cancer in a xenograft mouse model. Altogether, our study uncovers that p53 promotes glycolytic reprogramming and cuproptosis via circFRMD4A and suggests a potential combination strategy against cancers with wild-type p53.
    Keywords:  EWSR1; FRMD4A; PKM2; TCA cycle; cancer therapy; circular RNA; cuproptosis; glycolysis; p53; tumor metabolism
    DOI:  https://doi.org/10.1016/j.molcel.2024.11.013
  7. Anticancer Res. 2024 Dec;44(12): 5241-5252
    Mitochondrial Metabolism as a Potential Novel Therapeutic Target for Lung Adenocarcinoma.
    Makoto Fujiwara, Takahiro Mimae, Kei Kushitani, Norifumi Tsubokawa, Yoshihiro Miyata, Yukio Takeshima, Morihito Okada.
       BACKGROUND/AIM: Oxidative phosphorylation (OXPHOS) is implicated in cancer progression and metastasis. However, its role in lung adenocarcinoma (LUAD) is unknown. We assessed OXPHOS in LUAD cases and cell lines and investigated the effect of OXPHOS inhibition on LUAD cells.
    MATERIALS AND METHODS: The cases with high expression of OXPHOS-related genes and peroxisome proliferator-activated receptor gamma (PPAR-γ) were extracted using RNA-seq data from The Cancer Genome Atlas (TCGA) LUAD dataset and the clinicopathological features and survival were assessed. Resected LUAD specimens were stained for PPAR-γ. Real-time qPCR and western blot were used to examine the expression of OXPHOS- and glycolysis-related genes and proteins in four LUAD cell lines. Cell proliferation was evaluated in LUAD cells treated with OXPHOS inhibitors.
    RESULTS: The TCGA database analysis revealed that cases with high OXPHOS or PPAR-γ expression had a worse prognosis (p=0.07 and p=0.01, respectively). High OXPHOS cases were associated with lymph node metastasis (p<0.01). PPAR-γ was expressed only in the peripheral area of the papillary component of LUAD. We identified A549, HTB181 and H322 as OXPHOS-high type cells and H596 as OXPHOS-low type cells. Oligomycin treatment inhibited cell proliferation in the OXHOS-high cells (0.72-, 0.69-, and 0.77- fold change in oligomycin vs. DMSO, for A549, HTB181, and H322 cells, respectively, p<0.01) but not in the OXPHOS-low cells.
    CONCLUSION: High expression of OXPHOS-related genes and PPAR-γ is a poor prognostic factor in LUAD. The levels of OXPHOS vary among cases and within different areas of the tumor. Targeting OXPHOS metabolism may represent a novel therapeutic approach for treating LUAD.
    Keywords:  Lung neoplasms; adenocarcinoma of lung; oxidative phosphorylation; therapeutics
    DOI:  https://doi.org/10.21873/anticanres.17352
  8. ASN Neuro. 2024 ;16(1): 2422268
    Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells.
    Derek C Lee, Linh Ta, Purna Mukherjee, Tomas Duraj, Marek Domin, Bennett Greenwood, Srada Karmacharya, Niven R Narain, Michael Kiebish, Christos Chinopoulos, Thomas N Seyfried.
      Energy is necessary for tumor cell viability and growth. Aerobic glucose-driven lactic acid fermentation is a common metabolic phenotype seen in most cancers including malignant gliomas. This metabolic phenotype is linked to abnormalities in mitochondrial structure and function. A luciferin-luciferase bioluminescence ATP assay was used to measure the influence of amino acids, glucose, and oxygen on ATP content and viability in mouse (VM-M3 and CT-2A) and human (U-87MG) glioma cells that differed in cell biology, genetic background, and species origin. Oxygen consumption was measured using the Resipher system. Extracellular lactate and succinate were measured as end products of the glycolysis and glutaminolysis pathways, respectively. The results showed that: (1) glutamine was a source of ATP content irrespective of oxygen. No other amino acid could replace glutamine in sustaining ATP content and viability; (2) ATP content persisted in the absence of glucose and under hypoxia, ruling out substantial contribution through either glycolysis or oxidative phosphorylation (OxPhos) under these conditions; (3) Mitochondrial complex IV inhibition showed that oxygen consumption was not an accurate measure for ATP production through OxPhos. The glutaminase inhibitor, 6-diazo-5-oxo-L-norleucine (DON), reduced ATP content and succinate export in cells grown in glutamine. The data suggests that mitochondrial substrate level phosphorylation in the glutamine-driven glutaminolysis pathway contributes to ATP content in these glioma cells. A new model is presented highlighting the synergistic interaction between the high-throughput glycolysis and glutaminolysis pathways that drive malignant glioma growth and maintain ATP content through the aerobic fermentation of both glucose and glutamine.
    Keywords:  Fermentation; glioblastoma; glutaminolysis; mitochondrial substrate level phosphorylation; succinate
    DOI:  https://doi.org/10.1080/17590914.2024.2422268
  9. Biochim Biophys Acta Bioenerg. 2024 Nov 29. pii: S0005-2728(24)00498-5. [Epub ahead of print]1866(1): 149528
    Inside-out submitochondrial particles affect the mitochondrial permeability transition pore opening under conditions of mitochondrial dysfunction.
    Cristina Algieri, Antonia Cugliari, Patrycja Anna Glogowski, Silvia Granata, Micaela Fabbri, Fabiana Trombetti, Maria Laura Bacci, Salvatore Nesci.
      The inside-out submitochondrial particles (IO-SMPs) showed a strong protective effect against mitochondrial permeability transition pore (mPTP) opening in mitochondria isolated from swine hearts 3 h after explantation. The latter condition was used to emulate situation of mitochondrial damage. We identified that the protective effect of IO-SMPs cannot be attributed to a functional modulation of the enzymatic complexes involved in mPTP formation. Indeed, oxidative phosphorylation and F1FO-ATPase activity were not affected. Conversely, mPTP desensitization might be caused by structural modification. IO-SMP incorporation into the mitochondria can modulate the membrane-bound enzyme complexes' functionality, inducing F1FO-ATPase to be unable to carry out the conformational changes useful for mPTP opening. Thus, the data are a valid starting point for IO-SMP application in the treatment of impaired cardiovascular conditions supported by mPTP opening.
    Keywords:  F(1)F(O)-ATPase; Inside-out submitochondrial particles; Mitochondrial dysfunction; Mitochondrial permeability transition pore
    DOI:  https://doi.org/10.1016/j.bbabio.2024.149528
  10. J Cancer Biol. 2024 ;5(2): 65-75
    Proton Sensing GPCR's: The missing link to Warburg's Oncogenic Legacy?
    Jessica Cornell, Samantha Rea, Leif R Neitzel, Charles H Williams, Charles C Hong.
      A century after Otto Warburg's seminal discovery of aerobic glycolysis in cancer cells, a phenomenon dubbed the "Warburg effect", the mechanistic links between this metabolic rewiring and tumorigenesis remain elusive. Warburg postulated that this enhanced glucose fermentation to lactate, even in the presence of oxygen, stemmed from an "irreversible respiratory injury" intrinsic to cancer cells. While oxidative phosphorylation yields higher ATP, the Warburg effect paradoxically persists, suggesting that the excess lactate and acid production are worth the deficit. Since Warburg's discovery, it has been demonstrated that the acidic tumor microenvironment activates a myriad of pro-oncogenic phenotypes ranging from therapeutic resistance to immune escape. Here we propose that proton-sensing G-protein-coupled receptors (GPCRs) act as crucial heirs to Warburg's findings by transducing the acid signal from elevated glycolytic lactate into pro-oncogenic signals. The increased lactate production characteristic of the Warburg effect causes extracellular acidification. This acidic tumor microenvironment can activate proton-sensing GPCRs like GPR68, a proton-sensing receptor shown to stimulate proliferation, migration, and survival pathways in cancer cells. Such pH sensing is accomplished through protonation of key residues such as histidine, which causes a conformational change to activate various downstream signaling cascades including the MAPK, PI3K/Akt, Rho, and β-arrestin pathways implicated in tumor progression and therapeutic resistance. By coupling Warburg's "respiratory injury" to potent mitogenic signaling, proton-sensing GPCRs like GPR68 may unveil a longstanding mystery - why forgo efficient ATP generation? As heirs to Warburg's iconic metabolic observations, these proton sensors could represent novel therapeutic targets to disrupt the synergy between the Warburg effect and oncogenic signaling.
    DOI:  https://doi.org/10.46439/cancerbiology.5.066
  11. Nat Methods. 2024 Dec 05.
    The dynamics of hematopoiesis over the human lifespan.
    Hojun Li, Parker Côté, Michael Kuoch, Jideofor Ezike, Katie Frenis, Anton Afanassiev, Laura Greenstreet, Mayuri Tanaka-Yano, Giuseppe Tarantino, Stephen Zhang, Jennifer Whangbo, Vincent L Butty, Enrico Moiso, Marcelo Falchetti, Kate Lu, Guinevere G Connelly, Vivian Morris, Dahai Wang, Antonia F Chen, Giada Bianchi, George Q Daley, Salil Garg, David Liu, Stella T Chou, Aviv Regev, Edroaldo Lummertz da Rocha, Geoffrey Schiebinger, R Grant Rowe.
      Over a lifetime, hematopoietic stem cells (HSCs) adjust their lineage output to support age-aligned physiology. In model organisms, stereotypic waves of hematopoiesis have been observed corresponding to defined age-biased HSC hallmarks. However, how the properties of hematopoietic stem and progenitor cells change over the human lifespan remains unclear. To address this gap, we profiled individual transcriptome states of human hematopoietic stem and progenitor cells spanning gestation, maturation and aging. Here we define the gene expression networks dictating age-specific differentiation of HSCs and the dynamics of fate decisions and lineage priming throughout life. We additionally identifiy and functionally validate a fetal-specific HSC state with robust engraftment and multilineage capacity. Furthermore, we observe that classification of acute myeloid leukemia against defined transcriptional age states demonstrates that utilization of early life transcriptional programs associates with poor prognosis. Overall, we provide a disease-relevant framework for heterochronic orientation of stem cell ontogeny along the real time axis of the human lifespan.
    DOI:  https://doi.org/10.1038/s41592-024-02495-0
  12. Nature. 2024 Dec 04.
    Dietary fructose enhances tumour growth indirectly via interorgan lipid transfer.
    Ronald Fowle-Grider, Joe L Rowles, Isabel Shen, Yahui Wang, Michaela Schwaiger-Haber, Alden J Dunham, Kay Jayachandran, Matthew Inkman, Michael Zahner, Fuad J Naser, Madelyn M Jackstadt, Jonathan L Spalding, Sarah Chiang, Kyle S McCommis, Roland E Dolle, Eva T Kramer, Sarah M Zimmerman, George P Souroullas, Brian N Finck, Leah P Shriver, Charles K Kaufman, Julie K Schwarz, Jin Zhang, Gary J Patti.
      Fructose consumption has increased considerably over the past five decades, largely due to the widespread use of high-fructose corn syrup as a sweetener1. It has been proposed that fructose promotes the growth of some tumours directly by serving as a fuel2,3. Here we show that fructose supplementation enhances tumour growth in animal models of melanoma, breast cancer and cervical cancer without causing weight gain or insulin resistance. The cancer cells themselves were unable to use fructose readily as a nutrient because they did not express ketohexokinase-C (KHK-C). Primary hepatocytes did express KHK-C, resulting in fructolysis and the excretion of a variety of lipid species, including lysophosphatidylcholines (LPCs). In co-culture experiments, hepatocyte-derived LPCs were consumed by cancer cells and used to generate phosphatidylcholines, the major phospholipid of cell membranes. In vivo, supplementation with high-fructose corn syrup increased several LPC species by more than sevenfold in the serum. Administration of LPCs to mice was sufficient to increase tumour growth. Pharmacological inhibition of ketohexokinase had no direct effect on cancer cells, but it decreased circulating LPC levels and prevented fructose-mediated tumour growth in vivo. These findings reveal that fructose supplementation increases circulating nutrients such as LPCs, which can enhance tumour growth through a cell non-autonomous mechanism.
    DOI:  https://doi.org/10.1038/s41586-024-08258-3
  13. Sci Rep. 2024 12 03. 14(1): 30043
    Role of ATP citrate lyase and its complementary partner on fatty acid synthesis in gastric cancer.
    Chunlei Li, Wenxuan Liu, Youzhao Liu, Weixing Wang, Wenhong Deng.
      ATP citrate lyase (ACLY) and acyl-CoA short-chain synthetases 2 (ACSS2) are key enzymes in lipid metabolism. We explored the role of ACLY in gastric cancer (GC) and the effect of ACLY and ACSS2 compensation on GC growth. We used immunohistochemistry to verify the expression level of ACLY in GC, shRNA to stably knock down the expression level of ACLY in GC cells. The expression levels of lipid metabolizing enzymes were verified by qPCR and WB, and targeted lipidomics and quantification of lipid metabolism-related indicators helped us to understand the changes in lipid metabolism. Finally, subcutaneous graft tumors validate our findings from in vitro experiments. ACLY is upregulated in GC tissues, downregulation of ACLY reduced lipid accumulation and inhibited GC proliferation, migration, and invasion in vitro. ACSS2 maintains cell growth by compensatory elevation to maintain fatty acid synthesis activity in ACLY-depleted GC cells. Inhibition of ACSS2 enhanced the inhibitory effect of downregulation of ACLY on the growth of transplanted tumors in nude mice. Downregulation of ACLY inhibited GC cell growth in vitro and in vivo. ACSS2 was compensated to increase to maintain cell growth in ACLY-depleted GC cells.
    Keywords:  ACLY; ACSS2; Gastric cancer; Lipid metabolism; Treatment
    DOI:  https://doi.org/10.1038/s41598-024-81448-1
  14. Hemasphere. 2024 Dec;8(12): e70001
    Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma.
    Daniel Pölöske, Helena Sorger, Anna Schönbichler, Elvin D de Araujo, Heidi A Neubauer, Anna Orlova, Sanna H Timonen, Diaaeldin I Abdallah, Aleksandr Ianevski, Heikki Kuusanmäki, Marta Surbek, Elisabeth Heyes, Thomas Eder, Christina Wagner, Tobias Suske, Martin L Metzelder, Michael Bergmann, Maik Dahlhoff, Florian Grebien, Roman Fleck, Christine Pirker, Walter Berger, Emir Hadzijusufovic, Wolfgang R Sperr, Lukas Kenner, Peter Valent, Tero Aittokallio, Marco Herling, Satu Mustjoki, Patrick T Gunning, Richard Moriggl.
      The transcription factors STAT3, STAT5A, and STAT5B steer hematopoiesis and immunity, but their enhanced expression and activation promote acute myeloid leukemia (AML) or natural killer/T cell lymphoma (NKCL). Current therapeutic strategies focus on blocking upstream tyrosine kinases to inhibit STAT3/5, but these kinase blockers are not selective against STAT3/5 activation and frequent resistance causes relapse, emphasizing the need for targeted drugs. We evaluated the efficacy of JPX-0700 and JPX-0750 as dual STAT3/5 binding inhibitors promoting protein degradation. JPX-0700/-0750 decreased the mRNA and protein levels of STAT3/5 targets involved in cancer survival, metabolism, and cell cycle progression, exhibiting nanomolar to low micromolar efficacy. They induced cell death and growth arrest in both AML/NKCL cell lines and primary AML patient blasts. We found that both AML/NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in kinases, activating mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in anti-apoptotic, pro-proliferative, or epigenetic-modifying STAT3/5 targets. This emphasizes a vicious cycle for proliferation and survival through STAT3/5. Both JPX-0700/-0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models significantly, being well tolerated by mice. Synergistic cell death was induced upon combinatorial use with approved chemotherapeutics in AML/NKCL cells.
    DOI:  https://doi.org/10.1002/hem3.70001
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