bims-medica 2024-09-01 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–09–01
eightteen papers selected by
Brett Chrest, East Carolina University

Lactate helps cancer cells resist chemotherapy.
Hyperglycemia Stimulates the Irreversible Catabolism of Branched-Chain Amino Acids and Generation of Ketone Bodies by Cultured Human Astrocytes.
Tumour Microenvironment-Like Conditions Alter Pancreatic Cancer Cell Metabolism and Behaviour.
Phosphoenolpyruvate carboxykinase 2-mediated metabolism promotes lung tumorigenesis by inhibiting mitochondrial-associated apoptotic cell death.
Two-month ketogenic diet alters systemic and brain metabolism in middle-aged female mice.
Mitochondrial membrane lipids in the regulation of bioenergetic flux.
Unlocking the Potential: Caloric Restriction, Caloric Restriction Mimetics, and Their Impact on Cancer Prevention and Treatment.
Connecting Dots between Nucleotide Biosynthesis and DNA Lesion Repair/Bypass in Cancer.
Metabolic Plasticity of Glioblastoma Cells in Response to DHODH Inhibitor BAY2402234 Treatment.
Mitochondrial translation is the primary determinant of secondary mitochondrial complex I deficiencies.
Impact of Lifestyle Interventions on Gynecologic Cancers: Beyond Diet and Exercise.
Production and Multi-Parameter Live Cell Fluorescence Lifetime Imaging Microscopy (FLIM) of Multicellular Spheroids.
Conjoint analysis of succinylome and phosphorylome reveals imbalanced HDAC phosphorylation-driven succinylayion dynamic contibutes to lung cancer.
Stearoyl-CoA desaturase inhibition is toxic to acute myeloid leukemia displaying high levels of the de novo fatty acid biosynthesis and desaturation.
The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade.
BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models.
Mitochondrial serine catabolism safeguards maintenance of the hematopoietic stem cell pool in homeostasis and injury.
The Proton Leak of the Inner Mitochondrial Membrane Is Enlarged in Freshly Isolated Pancreatic Islets.

Nature. 2024 Aug 23.

Lactate helps cancer cells resist chemotherapy.



Keywords:  Cancer; Metabolism

DOI:  https://doi.org/10.1038/d41586-024-02731-9
Biomedicines. 2024 Aug 08. pii: 1803. [Epub ahead of print]12(8):

Hyperglycemia Stimulates the Irreversible Catabolism of Branched-Chain Amino Acids and Generation of Ketone Bodies by Cultured Human Astrocytes.

Eduard Gondáš, Eva Baranovičová, Jakub Šofranko, Radovan Murín.

  Astrocytes are considered to possess a noticeable role in brain metabolism and, as a partners in neuron-glia cooperation, to contribute to the synthesis, bioconversion, and regulation of the flux of substrates for neuronal metabolism. With the aim of investigating to what extent human astrocytes are metabolizing amino acids and by which compounds are they enriching their surroundings, we employed a metabolomics analysis of their culture media by 1H-NMR. In addition, we compared the composition of media with either 5 mM or 25 mM glucose. The quantitative analysis of culture media by 1H-NMR revealed that astrocytes readily dispose from their milieu glutamine, branched-chain amino acids, and pyruvate with significantly high rates, while they enrich the culture media with lactate, branched-chain keto acids, citrate, acetate, ketone bodies, and alanine. Hyperglycemia suppressed the capacity of astrocytes to release branched-chain 2-oxo acids, while stimulating the generation of ketone bodies. Our results highlight the active involvement of astrocytes in the metabolism of several amino acids and the regulation of key metabolic intermediates. The observed metabolic activities of astrocytes provide valuable insights into their roles in supporting neuronal function, brain metabolism, and intercellular metabolic interactions within the brain. Understanding the complex metabolic interactions between astrocytes and neurons is essential for elucidating brain homeostasis and the pathophysiology of neurological disorders. The observed metabolic activities of astrocytes provide hints about their putative metabolic roles in brain metabolism.

Keywords:  amino acid; astrocyte; branched-chain 2-oxo acid; branched-chain amino acid; euglycemia; hyperglycemia; isoleucine; ketone body; leucine; metabolomics; proton-nuclear magnetic resonance (1H-NMR); valine

DOI:  https://doi.org/10.3390/biomedicines12081803
Am J Physiol Cell Physiol. 2024 Aug 26.

Tumour Microenvironment-Like Conditions Alter Pancreatic Cancer Cell Metabolism and Behaviour.

Georgina Louise Gardner, Jeffrey Alan Stuart.

  The tumour microenvironment is complex and dynamic, characterized by poor vascularization, limited nutrient availability, hypoxia, and an acidic pH. This environment plays a critical role in driving cancer progression. However, standard cell culture conditions used to study cancer cell biology in vitro fail to replicate the in vivo environment of tumours. Recently, 'physiological' cell culture media that closely resemble human plasma have been developed (e.g., Plasmax, HPLM), along with more frequent adoption of physiological oxygen conditions (1-8% O2). Nonetheless, further refinement of tumour-specific culture conditions may be needed. In this study, we describe the development of a Tumour Microenvironment Medium (TMEM) based on murine pancreatic ductal adenocarcinoma (PDAC) tumour interstitial fluid. Using RNA-sequencing, we show that murine PDAC cells (KPCY) cultured in tumour-like conditions (TMEM, pH 7.0, 1.5% O2) exhibit profound differences in gene expression compared to plasma-like conditions (Mouse Plasma Medium, pH 7.4, 5% O2). Specifically, the expression of genes and pathways associated with cell migration, biosynthesis, angiogenesis, and epithelial-to-mesenchymal transition were altered, suggesting tumour-like conditions promote metastatic phenotypes and metabolic remodeling. Using functional assays to validate RNA-seq data, we confirmed increased motility at 1.5%O2/TMEM, despite reduced cell proliferation. Moreover, a hallmark shift to glycolytic metabolism was identified via measurement of glucose uptake/lactate production and mitochondrial respiration. Taken together, these findings demonstrate that growth in 1.5%O2/TMEM alters several biological responses in ways relevant to cancer biology, and more closely models hallmark cancerous phenotypes in culture. This highlights the importance of establishing tumour microenvironment-like conditions in standard cancer research.

Keywords:  Cell Culture; Metabolism; Oxygen; Physiological Media; Tumour Mircoenvironment

DOI:  https://doi.org/10.1152/ajpcell.00452.2024
Front Pharmacol. 2024 ;15 1434988

Phosphoenolpyruvate carboxykinase 2-mediated metabolism promotes lung tumorigenesis by inhibiting mitochondrial-associated apoptotic cell death.

Jing Zhang, Wenjuan He, Dongmei Liu, Wenyu Zhang, Huan Qin, Song Zhang, Ailan Cheng, Qiang Li, Feilong Wang.

   Background: It is unknown how cancer cells override apoptosis and maintain progression under nutrition-deprived conditions within the tumor microenvironment. Phosphoenolpyruvate carboxykinase (PEPCK or PCK) catalyzes the first rate-limiting reaction in gluconeogenesis, which is an essential metabolic alteration that is required for the proliferation of cancer cells under glucose-limited conditions. However, if PCK-mediated gluconeogenesis affects apoptotic cell death of non small cell lung cancer (NSCLC) and its potential mechanisms remain unknown.
Methods: RNA-seq, Western blot and RT-PCR were performed in A549 cell lines cultured in medium containing low or high concentrations of glucose (1 mM vs. 20 mM) to gain insight into how cancer cells rewire their metabolism under glucose-restriction conditions. Stable isotope tracing metabolomics technology (LC-MS) was employed to allow precise quantification of metabolic fluxes of the TCA cycle regulated by PCK2. Flow Cytometry was used to assess the rates of early and later apoptosis and mitochondrial ROS in NSCLC cells. Transwell assays and luciferase-based in vivo imaging were used to determine the role of PCK2 in migration and invasion of NSCLC cells. Xenotransplants on BALB/c nude mice to evaluate the effects of PCK2 on tumor growth in vivo. Western blot, Immunohistochemistry and TUNEL assays to evaluate the protein levels of mitochondrial apoptosis.
Results: This study report that the mitochondrial resident PCK (PCK2) is upregulated in dependent of endoplasmic reticulum stress-induced expression of activating transcription factor 4 (ATF4) upon glucose deprivation in NSCLC cells. Further, the study finds that PCK2-mediated metabolism is required to decrease the burden of the TCA cycles and oxidative phosphorylation as well as the production of mitochondrial reactive oxygen species. These metabolic alterations in turn reduce the activation of Caspase9-Caspase3-PARP signal pathway which drives apoptotic cell death. Importantly, silencing PCK2 increases apoptosis of NSCLC cells under low glucose condition and inhibits tumor growth both in vitro and in vivo.
Conclusion: In summary, PCK2-mediated metabolism is an important metabolic adaptation for NSCLC cells to acquire resistance to apoptosis under glucose deprivation.

Keywords:  lung tumorigenesis; metabolic reprogramming; mitochondrial apoptosis; phosphoenolpyruvate carboxykinase 2; reactive oxygen species

DOI:  https://doi.org/10.3389/fphar.2024.1434988
Geroscience. 2024 Aug 24.

Two-month ketogenic diet alters systemic and brain metabolism in middle-aged female mice.

Kirsten J Roslund, Jon J Ramsey, Jennifer M Rutkowsky, Zeyu Zhou, Carolyn M Slupsky.

  The ketogenic diet (KD) is a very low-carbohydrate, high-fat diet that reduces glucose catabolism and enhances β-oxidation and ketogenesis. While research in female rodents is limited, research in male rodents suggests that ketogenic interventions initiated at midlife may slow age-related cognitive decline, as well as preserve muscle mass and physical function later in life. This study aimed to investigate the effects of a KD on global metabolic changes in middle-aged females to inform potential mechanisms behind the anti-aging effects of this diet in an understudied sex. Targeted 1H-NMR metabolomics was conducted on serum, the liver, the kidney, and the gastrocnemius muscle, as well as the cortex and the hippocampal brain regions in 16-month-old female mice after a 2-month KD. Analysis of the serum and liver metabolome revealed that the 2-month KD resulted in increased concentrations of fatty acid catabolism metabolites, as well as system-wide elevations in ketones, consistent with the ketogenic phenotype. Metabolites involved in the glucose-alanine cycle were altered in the gastrocnemius muscle, serum and the liver. Other tissue-specific alterations were detected, including distinct effects on hepatic and renal one-carbon metabolism, as well as region specific differences in metabolism across hippocampal and cortical parts of the brain. Alterations to hippocampal metabolites involved in myelinogenesis could relate to the potential beneficial effects of a KD on memory.

Keywords:  Aging; Female; Ketogenic diet; Ketones; Metabolism; β-Hydroxybutyrate

DOI:  https://doi.org/10.1007/s11357-024-01314-w
Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00326-7. [Epub ahead of print]

Mitochondrial membrane lipids in the regulation of bioenergetic flux.

Stephen Thomas Decker, Katsuhiko Funai.

  Oxidative phosphorylation (OXPHOS) occurs through and across the inner mitochondrial membrane (IMM). Mitochondrial membranes contain a distinct lipid composition, aided by lipid biosynthetic machinery localized in the IMM and class-specific lipid transporters that limit lipid traffic in and out of mitochondria. This unique lipid composition appears to be essential for functions of mitochondria, particularly OXPHOS, by its effects on direct lipid-to-protein interactions, membrane properties, and cristae ultrastructure. This review highlights the biological significance of mitochondrial lipids, with a particular spotlight on the role of lipids in mitochondrial bioenergetics. We describe pathways for the biosynthesis of mitochondrial lipids and provide evidence for their roles in physiology, their implications in human disease, and the mechanisms by which they regulate mitochondrial bioenergetics.

Keywords:  bioenergetics; mitochondria; phospholipids

DOI:  https://doi.org/10.1016/j.cmet.2024.07.024
Metabolites. 2024 Jul 30. pii: 418. [Epub ahead of print]14(8):

Unlocking the Potential: Caloric Restriction, Caloric Restriction Mimetics, and Their Impact on Cancer Prevention and Treatment.

Ulises Edgardo De-Leon-Covarrubias, Jose Juan Perez-Trujillo, Sheila Adela Villa-Cedillo, Alejandra Guadalupe Martinez-Perez, Carlos Roberto Montes-de-Oca-Saucedo, Maria de Jesus Loera-Arias, Aracely Garcia-Garcia, Odila Saucedo-Cardenas, Roberto Montes-de-Oca-Luna.

  Caloric restriction (CR) and its related alternatives have been shown to be the only interventions capable of extending lifespan and decreasing the risk of cancer, along with a reduction in burden in pre-clinical trials. Nevertheless, the results from clinical trials have not been as conclusive as the pre-clinical results. Recognizing the challenges associated with long-term fasting, the application of caloric restriction mimetics (CRMs), pharmacological agents that mimic the molecular effects of CR, to harness the potential benefits while overcoming the practical limitations of fasting has resulted in an interesting alternative. This review synthesizes the findings of diverse clinical trials evaluating the safety and efficacy of CR and CRMs. In dietary interventions, a fast-mimicking diet was the most tolerated to reduce tumoral growth markers and chemotherapy side effects. CRMs were well tolerated, and metformin and aspirin showed the most promising effect in reducing cancer risk in a selected group of patients. The application of CR and/or CRMs shows promising effects in anti-cancer therapy; however, there is a need for more evidence to safely include these interventions in standard-of-care therapies.

Keywords:  aspirin; caloric restriction; caloric restriction mimetics; cancer; clinical trials; metformin

DOI:  https://doi.org/10.3390/metabo14080418
Biosci Rep. 2024 Aug 27. pii: BSR20231382. [Epub ahead of print]

Connecting Dots between Nucleotide Biosynthesis and DNA Lesion Repair/Bypass in Cancer.

Hunmin Jung, Jackson C Lin, Ayobami Oludare.

  Purine and pyrimidine nucleotides are crucial building blocks for the survival of cells, and there are layers of pathways to make sure a stable supply of them including de novo nucleotide biosynthesis. Fast-growing cells including cancer cells have high demand for nucleotide, and they highly utilize the nucleotide biosynthesis pathways. Due to the nature of the fast-growing cells, they tend to make more errors in replication compared to the normal cells. Naturally, DNA repair and DNA lesion bypass are heavily employed in cancer cells to ensure fidelity and completion of the replication without stalling. There have been a lot of drugs targeting cancer that mimic the chemical structures of the nucleobase, nucleoside, and nucleotides, and the resistance toward those drugs is a serious problem. Herein, we have reviewed some of the representative nucleotide analog anticancer agents such as 5-fluorouracil, specifically their mechanism of action and resistance is discussed. Also, we have chosen several enzymes in nucleotide biosynthesis, DNA repair, and DNA lesion bypass, and we have discussed the known and potential roles of these enzymes in maintaining genomic fidelity and cancer chemotherapy.

Keywords:  Cancer; DNA damage response; Nucleotide biosynthesis; drug discovery and design; drug resistance

DOI:  https://doi.org/10.1042/BSR20231382
Metabolites. 2024 Jul 27. pii: 413. [Epub ahead of print]14(8):

Metabolic Plasticity of Glioblastoma Cells in Response to DHODH Inhibitor BAY2402234 Treatment.

Ayenachew Bezawork-Geleta, Diane Moujalled, David P De Souza, Vinod K Narayana, James Dimou, Rodney Luwor, Matthew J Watt.

  Glioblastoma (IDH-wildtype) represents a formidable challenge in oncology, lacking effective chemotherapeutic or biological interventions. The metabolic reprogramming of cancer cells is a hallmark of tumor progression and drug resistance, yet the role of metabolic reprogramming in glioblastoma during drug treatment remains poorly understood. The dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 is a blood-brain barrier penetrant drug showing efficiency in in vivo models of many brain cancers. In this study, we investigated the effect of BAY2402234 in regulating the metabolic phenotype of EGFRWT and EGFRvIII patient-derived glioblastoma cell lines. Our findings reveal the selective cytotoxicity of BAY2402234 toward EGFRWT glioblastoma subtypes with minimal effect on EGFRvIII patient cells. At sublethal doses, BAY2402234 induces triglyceride synthesis at the expense of membrane lipid synthesis and fatty acid oxidation in EGFRWT glioblastoma cells, while these effects are not observed in EGFRvIII glioblastoma cells. Furthermore, BAY2402234 reduced the abundance of signaling lipid species in EGFRWT glioblastoma. This study elucidates genetic mutation-specific metabolic plasticity and efficacy in glioblastoma cells in response to drug treatment, offering insights into therapeutic avenues for precision medicine approaches.

Keywords:  brain cancer; lipid droplets; lipid metabolism

DOI:  https://doi.org/10.3390/metabo14080413
iScience. 2024 Aug 16. 27(8): 110560

Mitochondrial translation is the primary determinant of secondary mitochondrial complex I deficiencies.

Kristýna Čunátová, Marek Vrbacký, Guillermo Puertas-Frias, Lukáš Alán, Marie Vanišová, María José Saucedo-Rodríguez, Josef Houštěk, Erika Fernández-Vizarra, Jiří Neužil, Alena Pecinová, Petr Pecina, Tomáš Mráček.

  Individual complexes of the mitochondrial oxidative phosphorylation system (OXPHOS) are not linked solely by their function; they also share dependencies at the maintenance/assembly level, where one complex depends on the presence of a different individual complex. Despite the relevance of this "interdependence" behavior for mitochondrial diseases, its true nature remains elusive. To understand the mechanism that can explain this phenomenon, we examined the consequences of the aberration of different OXPHOS complexes in human cells. We demonstrate here that the complete disruption of each of the OXPHOS complexes resulted in a decrease in the complex I (cI) level and that the major reason for this is linked to the downregulation of mitochondrial ribosomal proteins. We conclude that the secondary cI defect is due to mitochondrial protein synthesis attenuation, while the responsible signaling pathways could differ based on the origin of the OXPHOS defect.

Keywords:  Biochemistry; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.110560
Am J Lifestyle Med. 2024 Jan-Feb;18(1):18(1): 7-20

Impact of Lifestyle Interventions on Gynecologic Cancers: Beyond Diet and Exercise.

Nathalie D McKenzie, Sarfraz Ahmad.

  A Lifestyle Medicine approach to compliment cancer care is less commonly researched or implemented for women with gynecologic cancers as compared to better funded malignancies such as breast, prostate, and colorectal. Yet, several gynecologic malignancies are linked to obesity, estrogen/metabolic signaling pathways, and altered tumor microenvironment which could benefit greatly from a lifestyle medicine program. Lifestyle medicine, an evidenced-based branch of science, has expanded to the prevention and treatment of disorders caused by lifestyle factors (including cancer). Modifiable lifestyle factors such as obesity, lack of physical activity/nutrient density, microbial dysbiosis, sleep disturbance, and chronic stressors contribute greatly to cancer morbidity and mortality worldwide. This overarching area of research is evolving with some subtopics in their infancy requiring further investigation. Modern tools have allowed for better understanding of mechanisms by which adiposity and inactivity affect tumor promoting signaling pathways as well as the local tumor environment. Through the evolving use of these sophisticated techniques, novel prognostic biomarkers have emerged to explore efficacy of pharmacologic and lifestyle interventions in cancer. This state-of-the-art review article appraises recent evidence for a lifestyle medicine approach, beyond diet and exercise, to optimize survivorship and quality of life for patients with gynecologic cancers and introduces the 8-week web-based comprehensive HEAL-GYN program.

Keywords:  gut microbiome; gynecologic cancers; lifestyle medicine; obesity and diet; stress and physical activity

DOI:  https://doi.org/10.1177/15598276221123764
J Vis Exp. 2024 Aug 09.

Production and Multi-Parameter Live Cell Fluorescence Lifetime Imaging Microscopy (FLIM) of Multicellular Spheroids.

Angela C Debruyne, Gabriele Ferrari, Hang Zhou, Nore Van Loon, Nina Heymans, Irina A Okkelman, Ruslan I Dmitriev.

Multicellular tumor spheroids are a popular 3D tissue microaggregate model for reproducing tumor microenvironment, testing and optimizing drug therapies and using bio- and nanosensors in a 3D context. Their ease of production, predictable size, growth, and observed nutrient and metabolite gradients are important to recapitulate the 3D niche-like cell microenvironment. However, spheroid heterogeneity and variability of their production methods can influence overall cell metabolism, viability, and drug response. This makes it difficult to choose the most appropriate methodology, considering the requirements in size, variability, needs of biofabrication, and use as in vitro 3D tissue models in stem and cancer cell biology. In particular, spheroid production can influence their compatibility with quantitative live microscopies, such as optical metabolic imaging, fluorescence lifetime imaging microscopy (FLIM), monitoring of spheroid hypoxia with nanosensors, or viability. Here, a number of conventional spheroid formation protocols are presented, highlighting their compatibility with the live widefield, confocal, and two-photon microscopies. The follow-up imaging to analysis pipeline with multiplexed autofluorescence FLIM and, using various types of cancer and stem cell spheroids, is also presented.

DOI: https://doi.org/10.3791/66845
Brief Bioinform. 2024 Jul 25. pii: bbae415. [Epub ahead of print]25(5):

Conjoint analysis of succinylome and phosphorylome reveals imbalanced HDAC phosphorylation-driven succinylayion dynamic contibutes to lung cancer.

Yifan Guo, Haoyu Wen, Zongwei Chen, Mengxia Jiao, Yuchen Zhang, Di Ge, Ronghua Liu, Jie Gu.

  Cancerous genetic mutations result in a complex and comprehensive post-translational modification (PTM) dynamics, in which protein succinylation is well known for its ability to reprogram cell metabolism and is involved in the malignant evolution. Little is known about the regulatory interactions between succinylation and other PTMs in the PTM network. Here, we developed a conjoint analysis and systematic clustering method to explore the intermodification communications between succinylome and phosphorylome from eight lung cancer patients. We found that the intermodification coorperation in both parallel and series. Besides directly participating in metabolism pathways, some phosphosites out of mitochondria were identified as an upstream regulatory modification directing succinylome dynamics in cancer metabolism reprogramming. Phosphorylated activation of histone deacetylase (HDAC) in lung cancer resulted in the removal of acetylation and favored the occurrence of succinylation modification of mitochondrial proteins. These results suggest a tandem regulation between succinylation and phosphorylation in the PTM network and provide HDAC-related targets for intervening mitochondrial succinylation and cancer metabolism reprogramming.

Keywords:  lung cancer; metabolism; phosphorylation; proteome; succinylation

DOI:  https://doi.org/10.1093/bib/bbae415
Leukemia. 2024 Aug 26.

Stearoyl-CoA desaturase inhibition is toxic to acute myeloid leukemia displaying high levels of the de novo fatty acid biosynthesis and desaturation.

Vilma Dembitz, Hannah Lawson, Richard Burt, Sirisha Natani, Céline Philippe, Sophie C James, Samantha Atkinson, Jozef Durko, Lydia M Wang, Joana Campos, Aoife M S Magee, Keith Woodley, Michael J Austin, Ana Rio-Machin, Pedro Casado, Findlay Bewicke-Copley, Giovanny Rodriguez Blanco, Diego Pereira-Martins, Lieve Oudejans, Emeline Boet, Alex von Kriegsheim, Juerg Schwaller, Andrew J Finch, Bela Patel, Jean-Emmanuel Sarry, Jerome Tamburini, Jan Jacob Schuringa, Lori Hazlehurst, John A Copland Iii, Mariia Yuneva, Barrie Peck, Pedro Cutillas, Jude Fitzgibbon, Kevin Rouault-Pierre, Kamil Kranc, Paolo Gallipoli.

Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients' outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential.

DOI: https://doi.org/10.1038/s41375-024-02390-9
Nat Metab. 2024 Aug;6(8): 1529-1548

The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade.

Yijian Qiu, Olivia T Stamatatos, Qingting Hu, Jed Ruiter Swain, Suzanne Russo, Ava Sann, Ana S H Costa, Sara Violante, David L Spector, Justin R Cross, Michael J Lukey.

Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis by glutaminase (GLS). However, this metabolic addiction can be lost in the tumour microenvironment, rendering GLS inhibitors ineffective in the clinic. Here we show that glutamine-addicted breast cancer cells adapt to chronic glutamine starvation, or GLS inhibition, via AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine, but α-ketoglutarate (α-KG). Mechanistically, we find that phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained α-KG production when glutamate is depleted. Breast cancer cells with resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied α-KG. Accordingly, inhibition of the SSP prevents adaptation to glutamine blockade, resulting in a potent drug synergism that suppresses breast tumour growth. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumour growth in a particular nutrient environment. This, in turn, has practical consequences for therapies targeting cancer metabolism.

DOI: https://doi.org/10.1038/s42255-024-01104-w
Nat Cancer. 2024 Aug 23.

BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models.

Ulrike Rauh, Guo Wei, Michael Serrano-Wu, Georgios Kosmidis, Stefan Kaulfuss, Franziska Siegel, Kai Thede, James McFarland, Christopher T Lemke, Nicolas Werbeck, Katrin Nowak-Reppel, Sabine Pilari, Stephan Menz, Matthias Ocker, Weiqun Zhang, Kyle Davis, Guillaume Poncet-Montange, Jennifer Roth, Douglas Daniels, Virendar K Kaushik, Brian Hubbard, Karl Ziegelbauer, Todd R Golub.

The MCL1 gene is frequently amplified in cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to the current standard of care. Therefore, MCL1 is an attractive anticancer target. Here we describe BRD-810 as a potent and selective MCL1 inhibitor and its key design principle of rapid systemic clearance to potentially minimize area under the curve-driven toxicities associated with MCL1 inhibition. BRD-810 induced rapid cell killing within 4 h in vitro but, in the same 4-h window, had no impact on cell viability or troponin I release in human induced pluripotent stem cell-derived cardiomyocytes, even at suprapharmacologic concentrations. In vivo BRD-810 induced efficacy in xenograft hematological and solid tumor models despite the short residence time of BRD-810 in plasma. In totality, our data support the hypothesis that short-term inhibition of MCL1 with BRD-810 can induce apoptosis in tumor cells while maintaining an acceptable safety profile. We, therefore, intend to advance BRD-810 to clinical trials.

DOI: https://doi.org/10.1038/s43018-024-00814-0
Cell Stem Cell. 2024 Aug 21. pii: S1934-5909(24)00285-6. [Epub ahead of print]

Mitochondrial serine catabolism safeguards maintenance of the hematopoietic stem cell pool in homeostasis and injury.

Changhong Du, Chaonan Liu, Kuan Yu, Shuzhen Zhang, Zeyu Fu, Xinliang Chen, Weinian Liao, Jun Chen, Yimin Zhang, Xinmiao Wang, Mo Chen, Fang Chen, Mingqiang Shen, Cheng Wang, Shilei Chen, Song Wang, Junping Wang.

  Hematopoietic stem cells (HSCs) employ a very unique metabolic pattern to maintain themselves, while the spectrum of their metabolic adaptations remains incompletely understood. Here, we uncover a distinct and heterogeneous serine metabolism within HSCs and identify mouse HSCs as a serine auxotroph whose maintenance relies on exogenous serine and the ensuing mitochondrial serine catabolism driven by the hydroxymethyltransferase 2 (SHMT2)-methylene-tetrahydrofolate dehydrogenase 2 (MTHFD2) axis. Mitochondrial serine catabolism primarily feeds NAD(P)H generation to maintain redox balance and thereby diminishes ferroptosis susceptibility of HSCs. Dietary serine deficiency, or genetic or pharmacological inhibition of the SHMT2-MTHFD2 axis, increases ferroptosis susceptibility of HSCs, leading to impaired maintenance of the HSC pool. Moreover, exogenous serine protects HSCs from irradiation-induced myelosuppressive injury by fueling mitochondrial serine catabolism to mitigate ferroptosis. These findings reframe the canonical view of serine from a nonessential amino acid to an essential niche metabolite for HSC pool maintenance.

Keywords:  NADPH; SHMT2; ferroptosis; hematopoietic stem cell; heterogeneity; ionizing radiation; mitochondrial serine catabolism; myelosuppressive injury

DOI:  https://doi.org/10.1016/j.stem.2024.07.009
Biomedicines. 2024 Aug 02. pii: 1747. [Epub ahead of print]12(8):

The Proton Leak of the Inner Mitochondrial Membrane Is Enlarged in Freshly Isolated Pancreatic Islets.

Mohammed Alshafei, Mai Morsi, Julia Reschke, Ingo Rustenbeck.

  In a number of investigations on the mechanism of the metabolic amplification of insulin secretion, differences between the response of freshly isolated islets and of islets cultured for one day have been observed. Since no trivial explanation like insufficient numbers of viable cells after cell culture could be found, a more thorough investigation into the mechanisms responsible for the difference was made, concentrating on the function of the mitochondria as the site where the metabolism of nutrient stimulators of secretion forms the signals impacting on the transport and fusion of insulin granules. Using combinations of inhibitors of oxidative phosphorylation, we come to the conclusion that the mitochondrial membrane potential is lower and the exchange of mitochondrial reducing equivalents is faster in freshly isolated islets than in cultured islets. The significantly higher rate of oxygen consumption in fresh islets than in cultured islets (13 vs. 8 pmol/min/islet) was not caused by a different activity of the F1F0-ATPase, but by a larger proton leak. These observations raise the questions as to whether the proton leak is a physiologically regulated pathway and whether its larger size in fresh islets reflects the working condition of the islets within the pancreas.

Keywords:  insulin secretion; metabolic amplification; mitochondrial membrane potential; oxygen consumption; pancreatic islets

DOI:  https://doi.org/10.3390/biomedicines12081747