bims-medica 2025-02-16 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–02–16
nine papers selected by
Brett Chrest, Wake Forest University

Disruption of redox balance in glutaminolytic triple negative breast cancer by inhibition of glutaminase and glutamate export.
Subcellular Compartmentalization of Glucose Mediated Insulin Secretion.
The role of dietary sugars in cancer risk: A comprehensive review of current evidence.
Ketogenic diet induces an inflammatory reactive astrocytes phenotype reducing glioma growth.
Dietary Restrictions and Cancer Prevention: State of the Art.
Persistent post-remission clonal hematopoiesis shapes the relapse trajectories of acute myeloid leukemia.
Lactate controls cancer stemness and plasticity through epigenetic regulation.
Lipids Metabolism Inhibition Antiproliferative Synergy with 5-Fluorouracil in Human Colorectal Cancer Model.
A relative metabolic flux analysis model of glucose anaplerosis.

Neoplasia. 2025 Feb 11. pii: S1476-5586(25)00015-6. [Epub ahead of print]61 101136

Disruption of redox balance in glutaminolytic triple negative breast cancer by inhibition of glutaminase and glutamate export.

Hoon Choi, Mamta Gupta, Arjun Sengupta, Emma E Furth, Christopher Hensley, Aalim M Weljie, Hsiaoju Lee, Yu-Ting Lu, Austin Pantel, David Mankoff, Rong Zhou.

  Resistance to chemotherapy is an important challenge in the clinical management of triple-negative breast cancer (TNBC). Utilization of the amino acid glutamine as a key nutrient is a metabolic signature of TNBC featuring high glutaminase (GLS) activity and a large pool of cellular glutamate, which mediates intracellular enrichment of cystine via xCT (SLC7A11) antiporter activity. To overcome chemo-resistant TNBC, we identified a strategy of dual metabolic inhibition of GLS and xCT to sensitize resistant TNBC cells to chemotherapy. We successfully tested this strategy in a human TNBC line and its chemoresistant variant in vitro and their xenograft models in vivo. Key findings of our study include: 1. Dual metabolic inhibition induced pronounced reductions of cellular glutathione accompanying significant increases of cellular superoxide level in both parent and resistant TNBC cells. While GLS and xCT inhibition did not directly kill cells via apoptosis, they potentiated doxorubicin (DOX) and cisplatin (CIS) to induce remarkably higher levels of apoptosis than DOX or CIS alone. 2. Although the resistant TNBC cells exhibited higher capacity to mitigate oxidative stress than the parent cells, their resistance was overcome by dual metabolic inhibition combined with DOX or CIS. 3. In vivo efficacy and safety of the triple combination (GLS and xCT inhibition plus DOX or CIS) were demonstrated in both chemo sensitive and resistant TNBC tumors in mice. In conclusion, GLS and xCT inhibition resulted in unmitigated oxidative stress due to depletion of glutathione, representing a promising strategy to overcome chemoresistance in glutamine-dependent TNBC.

Keywords:  Chemo-resistance; Glutaminase; Glutathione; Redox; Triple-negative breast cancer; cystine transporter

DOI:  https://doi.org/10.1016/j.neo.2025.101136
Cells. 2025 Jan 29. pii: 198. [Epub ahead of print]14(3):

Subcellular Compartmentalization of Glucose Mediated Insulin Secretion.

Zhongying Wang, Tatyana Gurlo, Leslie S Satin, Scott E Fraser, Peter C Butler.

  Regulation of blood glucose levels depends on the property of beta cells to couple glucose sensing with insulin secretion. This is accomplished by the concentration-dependent flux of glucose through glycolysis and oxidative phosphorylation, generating ATP. The resulting rise in cytosolic ATP/ADP inhibits KATP channels, inducing membrane depolarization and Ca2+ influx, which prompts insulin secretion. Evidence suggests that this coupling of glucose sensing with insulin secretion may be compartmentalized in the submembrane regions of the beta cell. We investigated the subcellular responses of key components involved in this coupling and found mitochondria in the submembrane zone, some tethered to the cytoskeleton near capillaries. Using Fluorescent Lifetime Imaging Microscopy (FLIM), we observed that submembrane mitochondria were the fastest to respond to glucose. In the most glucose-responsive beta cells, glucose triggers rapid, localized submembrane increases in ATP and Ca2+ as synchronized ~4-min oscillations, consistent with pulsatile insulin release after meals. These findings are consistent with the hypothesis that glucose sensing is coupled with insulin secretion in the submembrane zone of beta cells. This zonal adaptation would enhance both the speed and energy efficiency of beta cell responses to glucose, as only a subset of the most accessible mitochondria would be required to trigger insulin secretion.

Keywords:  ATP; KATP channel; beta cells; calcium; compartmentalization; insulin; mitochondria; oxidative phosphorylation; pulsatile secretion; submembrane

DOI:  https://doi.org/10.3390/cells14030198
Cancer Treat Res Commun. 2025 Feb 03. pii: S2468-2942(25)00014-0. [Epub ahead of print]43 100876

The role of dietary sugars in cancer risk: A comprehensive review of current evidence.

Nazmul Hasan, Omid Yazdanpanah, Barbod Khaleghi, David J Benjamin, Arash Rezazadeh Kalebasty.

   GOAL OF THE REVIEW: The objective of this review is to conduct a thorough examination of the current evidence regarding the correlation between dietary sugar intake and cancer risk. This will encompass the biological mechanisms, the diverse effects of various sugar types, and the potential implications for cancer treatment and dietary recommendations.
INTRODUCTION: Nutritional and epidemiological studies now focus much on the relationship between sugar intake and cancer. The data is still conflicting even if some studies imply that excessive sugar intake can help cancer develop by means of insulin resistance and chronic inflammation.
DISCUSSION: Through processes such as insulin resistance, inflammation, and angiogenesis, dietary sugars can impact carcinogenesis. Fructose increases angiogenesis by VEGF overexpression while glucose stimulates cancer cell growth by the Warburg effect. Contradicting data on the contribution of sugar to cancer emphasizes the need of consistent research techniques to simplify these dynamics. Reducing added sugar consumption in cancer prevention and management is especially crucial given that sugar affects immune function and treatment resistance, which could lead to new therapeutic targets.
CONCLUSION: High sugar intake is linked to mechanisms such as the Warburg effect, insulin resistance, and chronic inflammation, which may contribute to cancer risk under specific conditions. However, the evidence is not universally conclusive, and additional large-scale, long-term research are required to better understand these processes. To help in cancer prevention and management, public health guidelines should emphasize reducing added sugar consumption and promoting a balanced diet rich in natural foods.

Keywords:  Cancer; Insulin; Metabolism; Nutrition; Sugar

DOI:  https://doi.org/10.1016/j.ctarc.2025.100876
Cell Mol Life Sci. 2025 Feb 08. 82(1): 73

Ketogenic diet induces an inflammatory reactive astrocytes phenotype reducing glioma growth.

Maria Rosito, Javeria Maqbool, Alice Reccagni, Micol Mangano, Tiziano D'Andrea, Arianna Rinaldi, Giovanna Peruzzi, Beatrice Silvestri, Alessandro Rosa, Flavia Trettel, Giuseppina D'Alessandro, Myriam Catalano, Sergio Fucile, Cristina Limatola.

  The use of a ketogenic diet (KD) in glioma is currently tested as an adjuvant treatment in standard chemotherapy regimens. The metabolic shift induced by the KD leads to the generation of ketone bodies that can influence glioma cells and the surrounding microenvironment, but the mechanisms have not yet been fully elucidated. Here, we investigated the potential involvement of glial cells as mediators of the KD-induced effects on tumor growth and survival rate in glioma-bearing mice. Specifically, we describe that exposing glioma-bearing mice to a KD or to β-hydroxybutyrate (β-HB), one of the main KD metabolic products, reduced glioma growth in vivo, induced a pro-inflammatory phenotype in astrocytes and increased functional glutamate transporters. Moreover, we described increased intracellular basal Ca2+ levels in GL261 glioma cells treated with β-HB or co-cultured with astrocytes. These data suggest that pro-inflammatory astrocytes triggered by β-HB can be beneficial in counteracting glioma proliferation and neuronal excitotoxicity, thus protecting brain parenchyma.

Keywords:  Astrocytes; Astrogliosis; Glioma; Ketogenic diet; Microglia; Pro-inflammatory astrocytes; β-HB

DOI:  https://doi.org/10.1007/s00018-025-05600-4
Nutrients. 2025 Jan 29. pii: 503. [Epub ahead of print]17(3):

Dietary Restrictions and Cancer Prevention: State of the Art.

Greta Caprara, Rani Pallavi, Shalini Sanyal, Pier Giuseppe Pelicci.

  Worldwide, almost 10 million cancer deaths occurred in 2022, a number that is expected to rise to 16.3 million by 2040. Primary prevention has long been acknowledged as a crucial approach to reducing cancer incidence. In fact, between 30 and 50 percent of all tumors are known to be preventable by eating a healthy diet, staying active, avoiding alcohol, smoking, and being overweight. Accordingly, many international organizations have created tumor prevention guidelines, which underlie the importance of following a diet that emphasizes eating plant-based foods while minimizing the consumption of red/processed meat, sugars, processed foods, and alcohol. However, further research is needed to define the relationship between the effect of specific diets or nutritional components on cancer prevention. Interestingly, reductions in food intake and dietetic restrictions can extend the lifespan of yeast, nematodes, flies, and rodents. Despite controversial results in humans, those approaches have the potential to ameliorate health via direct and indirect effects on specific signaling pathways involved in cancer onset. Here, we describe the latest knowledge on the cancer-preventive potential of dietary restrictions and the biochemical processes involved. Molecular, preclinical, and clinical studies evaluating the effects of different fasting strategies will also be reviewed.

Keywords:  calorie restriction; cancer; diet; dietary restriction; fasting; microbiota; nutrition; overweight; prevention

DOI:  https://doi.org/10.3390/nu17030503
Blood Adv. 2025 Feb 12. pii: bloodadvances.2024015149. [Epub ahead of print]

Persistent post-remission clonal hematopoiesis shapes the relapse trajectories of acute myeloid leukemia.

Ryan D Chow, Priya Velu, Safoora Deihimi, Jonathan P Belman, Angela Youn, Nisargbhai Shah, Selina M Luger, Martin P Carroll, Jennifer Jd Morrissette, Robert L Bowman.

Mutations found in AML such as DNMT3A, TET2 and ASXL1 can be found in the peripheral blood of healthy adults - a phenomenon termed clonal hematopoiesis (CH). These mutations are thought to represent the earliest genetic events in the evolution of AML. Genomic studies on samples acquired at diagnosis, remission, and at relapse have demonstrated significant stability of CH mutations following induction chemotherapy. Meanwhile, later mutations in genes such as NPM1 and FLT3, have been shown to contract at remission and in the case of FLT3 often are absent at relapse. We sought to understand how early CH mutations influence subsequent evolutionary trajectories throughout remission and relapse in response to induction chemotherapy. We assembled a retrospective cohort of patients diagnosed with de novo AML at our institution that underwent genomic sequencing at diagnosis, remission and/or relapse (total n=182 patients). FLT3 and NPM1 mutations were generally eliminated at complete remission but subsequently reemerged upon relapse, whereas DNMT3A, TET2 and ASXL1 mutations often persisted through remission. CH-related mutations exhibited distinct constellations of co-occurring genetic alterations, with NPM1 and FLT3 mutations enriched in DNMT3Amut AML, while CBL and SRSF2 mutations were enriched in TET2mut and ASXL1mut AML, respectively. In the case of NPM1 and FLT3 mutations, these differences vanished at the time of complete remission yet readily reemerged upon relapse, indicating the reproducible nature of these genetic interactions. Thus, CH-associated mutations that likely precede malignant transformation subsequently shape the evolutionary trajectories of AML through diagnosis, therapy, and relapse.

DOI: https://doi.org/10.1182/bloodadvances.2024015149
Cell Metab. 2025 Feb 04. pii: S1550-4131(25)00002-6. [Epub ahead of print]

Lactate controls cancer stemness and plasticity through epigenetic regulation.

Nguyen T B Nguyen, Sira Gevers, Rutger N U Kok, Lotte M Burgering, Hannah Neikes, Ninouk Akkerman, Max A Betjes, Marlies C Ludikhuize, Can Gulersonmez, Edwin C A Stigter, Yvonne Vercoulen, Jarno Drost, Hans Clevers, Michiel Vermeulen, Jeroen S van Zon, Sander J Tans, Boudewijn M T Burgering, Maria J Rodríguez Colman.

  Tumors arise from uncontrolled cell proliferation driven by mutations in genes that regulate stem cell renewal and differentiation. Intestinal tumors, however, retain some hierarchical organization, maintaining both cancer stem cells (CSCs) and cancer differentiated cells (CDCs). This heterogeneity, coupled with cellular plasticity enabling CDCs to revert to CSCs, contributes to therapy resistance and relapse. Using genetically encoded fluorescent reporters in human tumor organoids, combined with our machine-learning-based cell tracker, CellPhenTracker, we simultaneously traced cell-type specification, metabolic changes, and reconstructed cell lineage trajectories during tumor organoid development. Our findings reveal distinctive metabolic phenotypes in CSCs and CDCs. We find that lactate regulates tumor dynamics, suppressing CSC differentiation and inducing dedifferentiation into a proliferative CSC state. Mechanistically, lactate increases histone acetylation, epigenetically activating MYC. Given that lactate's regulation of MYC depends on the bromodomain-containing protein 4 (BRD4), targeting cancer metabolism and BRD4 inhibitors emerge as a promising strategy to prevent tumor relapse.

Keywords:  cancer metabolism; cell plasticity; cell types; cell-cell interactions; differentiation; heterogeneity; live imaging; organoids; single-cell tracking; stem cells

DOI:  https://doi.org/10.1016/j.cmet.2025.01.002
Int J Mol Sci. 2025 Jan 30. pii: 1186. [Epub ahead of print]26(3):

Lipids Metabolism Inhibition Antiproliferative Synergy with 5-Fluorouracil in Human Colorectal Cancer Model.

Judyta Zabielska, Ewa Stelmanska, Sylwia Szrok-Jurga, Jarosław Kobiela, Aleksandra Czumaj.

  Colorectal cancer (CRC) is recognized as the third most lethal cancer worldwide. While existing treatment options demonstrate considerable efficacy, they are often constrained by non-selectivity and substantial side effects. Recent studies indicate that lipid metabolism significantly influences carcinogenesis, highlighting it as a promising avenue for developing targeted anticancer therapies. The purpose of the study was to see if acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and stearoyl-CoA 9-desaturase (SCD1) are good metabolic targets and whether the use of inhibitors of these enzymes together with 5-fluorouracil (5-FU) would have a synergistic effect on CRC cell viability. To confirm that the correct lipid targets were chosen, the expression levels of ACAT1, HMGCR, and SCD1 were examined in CRC patients and cell models. At first, each compound (Avasimibe, Lovastatin, MF-438, and 5-FU was tested separately, and then each inhibitor was paired with 5-FU to assess the synergistic effect on cell viability. Gene expression of selected enzymes significantly increased in tissue samples obtained from CRC patients and cancer cell lines (HT-29). Inhibition of any of the selected enzymes reduced CRC cell growth in a dose-dependent manner. More importantly, the combination of 5-FU + Avasimibe (an ACAT1 inhibitor) and 5-FU + MF-438 (an SCD1 inhibitor) produced a stronger antiproliferative effect than the inhibitors alone. 5-FU combined either with Avasimibe or MF-438 showed a synergistic effect with an HSA score of 47.00 at a dose of 0.3 + 30 µM, respectively (2.66% viability rate vs. 46%; p < 0.001), and 39.34 at a dose of 0.3 + 0.06 µM (46% vs. 10.33%; p < 0.001), respectively. The association of 5-FU with Lovastatin (HMGCR inhibitor) did not significantly impact CRC cell viability in a synergistic manner. Inhibition of lipid metabolism combined with standard chemotherapy is a promising strategy that reduces CRC cell viability and allows for the use of a lower drug dose. The combination of 5-FU and Avasimibe has the greatest therapeutic potential among studied compounds.

Keywords:  CRC cells; avasimibe; cell viability; colorectal cancer; combination therapy; lipid metabolism

DOI:  https://doi.org/10.3390/ijms26031186
Arch Biochem Biophys. 2025 Feb 06. pii: S0003-9861(25)00043-8. [Epub ahead of print] 110330

A relative metabolic flux analysis model of glucose anaplerosis.

Heesoo Jeong, Nathaniel M Vacanti.

  Glucose provides substrate for the predominant anaplerotic pathway which involves the activity of pyruvate carboxylase (PC). PC-mediated anaplerosis has been extensively studied as a metabolic regulator in glycolytic cells during tumorigenesis and metastasis. Herein, inaccuracies in established methods to measure relative intracellular flux through PC are highlighted and a compartmentalized condensed metabolic network (CCMN) is used to resolve the total malate pool into relative contributions from PC and other sources by metabolic flux analysis (MFA) with [U-13C6]glucose tracing. Performance of the CCMN method is evaluated in breast cancer cell lines that are exposed to small molecules targeting metabolism. Across conditions and cell lines, the CCMN approach yields results nearest to an accepted gold-standard methodology, using [3-13C]glucose, or even exposes the gold standard's limitations. The CCMN method does not require a separate experiment with a much more costly and generally less informative metabolic tracer, such as [3-13C]glucose, and in some cases, may outperform its application.

Keywords:  breast cancer; metabolic flux; pyruvate carboxylase; stable-isotope tracing; systems biology

DOI:  https://doi.org/10.1016/j.abb.2025.110330