bims-glucam 2023-09-17 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–09–17
eightteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Combining single-cell and transcriptomic analysis revealed the immunomodulatory effect of GOT2 on a glutamine-dependent manner in cutaneous melanoma.
The Role of Stroma in Cancer Metabolism.
Effect of differential deprivation of nutrients on cellular proliferation, oxidative stress, mitochondrial function, and cell migration in MDA-MB-231, HepG2, and HeLa cells.
Tumor microenvironmental nutrients, cellular responses, and cancer.
Bioinformatics and machine learning were used to validate glutamine metabolism-related genes and immunotherapy in osteoporosis patients.
Canagliflozin reduces chemoresistance in hepatocellular carcinoma through PKM2-c-Myc complex-mediated glutamine starvation.
Amino acid metabolism in health and disease.
Screening in serum-derived medium reveals differential response to compounds targeting metabolism.
SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism.
Glutamine deficiency drives transforming growth factor-β signaling activation that gives rise to myofibroblastic carcinoma-associated fibroblasts.
Sulforaphane rewires central metabolism to support antioxidant response and achieve glucose homeostasis.
Nanorod/nanodisk-integrated liquid crystalline systems for starvation, chemodynamic, and photothermal therapy of cancer.
Mathematical reconstruction of the metabolic network in an in-vitro multiple myeloma model.
CK1δ/CK1ε Signaling Sustains Mitochondrial Metabolism and Cell Survival in Multiple Myeloma.
Crosstalk between hepatic glutathione efflux and tumor targeting of ICG-conjugated gold nanoparticles.
A study on metabolic characteristics and metabolic markers of gastrointestinal tumors.
Fumarate hydratase (FH) and cancer: a paradigm of oncometabolism.
Removal of gemcitabine-induced senescent cancer cells by targeting glutaminase1 improves the therapeutic effect in pancreatic ductal adenocarcinoma.

Front Pharmacol. 2023 ;14 1241454

Combining single-cell and transcriptomic analysis revealed the immunomodulatory effect of GOT2 on a glutamine-dependent manner in cutaneous melanoma.

Lebin Song, Xiyi Wei, Xi Zhang, Yan Lu.

  Background: Reprogramming in glutamine metabolism is a hallmark of cancers, while its role in cutaneous melanoma has not been studied at great length. Methods: Here, we constructed a glutamine metabolism-related prognostic signature in cutaneous melanoma with a variety of bioinformatics methods according to the glutamine metabolism regulatory molecules. Moreover, experimental verification was carried out for the key gene. Results: We have identified two subgroups of cutaneous melanoma patients, each with different prognoses, immune characteristics, and genetic mutations. GOT2 was the most concerned key gene among the model genes. We verified its role in promoting tumor cell proliferation by CCK-8 and clone formation assays. Conclusion: Our study cast new light on the prognosis of cutaneous melanoma, and the internal mechanism regulating glutamine metabolism of GOT2 may provide a new avenue for treating the cutaneous melanoma disease precisely.

Keywords:  GOT2; cutaneous melanoma; genetic mutation; glutamine metabolism; prognostic model; tumor immune

DOI:  https://doi.org/10.3389/fphar.2023.1241454
Cold Spring Harb Perspect Med. 2023 Sep 11. pii: a041540. [Epub ahead of print]

The Role of Stroma in Cancer Metabolism.

Alec C Kimmelman, Mara H Sherman.

The altered metabolism of tumor cells is a well-known hallmark of cancer and is driven by multiple factors such as mutations in oncogenes and tumor suppressor genes, the origin of the tissue where the tumor arises, and the microenvironment of the tumor. These metabolic changes support the growth of cancer cells by providing energy and the necessary building blocks to sustain proliferation. Targeting these metabolic alterations therapeutically is a potential strategy to treat cancer, but it is challenging due to the metabolic plasticity of tumors. Cancer cells have developed ways to scavenge nutrients through autophagy and macropinocytosis and can also form metabolic networks with stromal cells in the tumor microenvironment. Understanding the role of the tumor microenvironment in tumor metabolism is crucial for effective therapeutic targeting. This review will discuss tumor metabolism and the contribution of the stroma in supporting tumor growth through metabolic interactions.

DOI: https://doi.org/10.1101/cshperspect.a041540
3 Biotech. 2023 Oct;13(10): 339

Effect of differential deprivation of nutrients on cellular proliferation, oxidative stress, mitochondrial function, and cell migration in MDA-MB-231, HepG2, and HeLa cells.

Abhinav Prasad, Ashim Chandra Roy, Komal Priya, Ramovatar Meena, Ilora Ghosh.

  Cancerous cells display metabolic engineering through enhanced utilization of nutrients to support their increased requirements for proliferation, bioenergetics, biosynthesis, redox homeostasis, and cell signaling. To investigate the extent to which malignant cells rely on glycolysis and glutaminolysis, the effects of differential deprivation of nutrients such as d-glucose, l-glutamine, and pyruvate on proliferation, morphology, cell cycle, oxidative stress, mitochondrial function, autophagic vacuole formation, and migration in MDA-MB-231, HepG2, and HeLa cells were investigated in this study. Cell viability assay, cell morphology, and ATP assay showed higher dependence of MDA-MB-231 and HepG2 cells on glucose and glutamine, respectively, for cell survival, growth, ATP production, and proliferation, while HeLa cells were equally dependent on both. However, the combination of all three nutrients displayed maximum proliferation. Differential deprivation of glucose in the absence of glutamine resulted in G0/G1 plus G2/M arrest in MDA-MB-231, whereas G0/G1 arrest in HepG2 and S-phase arrest in HeLa cells occurred at 48 h. Although the differential withdrawal of nutrients revealed a varying degree of effect dependent on cell type, nutrient type, nutrient concentrations, and deprivation time, a general trend of increased oxidative stress, loss of mitochondrial membrane potential, and ATP and antioxidant (GSH) depletion led to mitochondrial dysfunction in all three cell lines and inhibition of cell migration in MDA-MB-231 and HeLa cells at 48 h. Extreme deprivation of nutrients formed autophagic vacuoles. Importantly, normal cells (HEK293) remained unaffected under most of the nutrient-deprived conditions examined. This study enhances our understanding of the impact of differential nutrient deprivation on critical characteristics of cancer cells, contributing to the development of metabolism-based effective anticancer strategies.
Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03759-w.

Keywords:  Cancer; Cell cycle arrest; Cell death; Glucose and glutamine; Metabolic stress; Mitochondrial function

DOI:  https://doi.org/10.1007/s13205-023-03759-w
Cell Chem Biol. 2023 Sep 01. pii: S2451-9456(23)00281-7. [Epub ahead of print]

Tumor microenvironmental nutrients, cellular responses, and cancer.

Graham P Lobel, Yanqing Jiang, M Celeste Simon.

  Over the last two decades, the rapidly expanding field of tumor metabolism has enhanced our knowledge of the impact of nutrient availability on metabolic reprogramming in cancer. Apart from established roles in cancer cells themselves, various nutrients, metabolic enzymes, and stress responses are key to the activities of tumor microenvironmental immune, fibroblastic, endothelial, and other cell types that support malignant transformation. In this article, we review our current understanding of how nutrient availability affects metabolic pathways and responses in both cancer and "stromal" cells, by dissecting major examples and their regulation of cellular activity. Understanding the relationship of nutrient availability to cellular behaviors in the tumor ecosystem will broaden the horizon of exploiting novel therapeutic vulnerabilities in cancer.

Keywords:  Cancer metabolism; cancer therapeutics; cancer-associated fibroblasts; immune cell metabolism; nutrient exchange; stress responses; tumor microenvironment

DOI:  https://doi.org/10.1016/j.chembiol.2023.08.011
J Orthop Surg Res. 2023 Sep 14. 18(1): 685

Bioinformatics and machine learning were used to validate glutamine metabolism-related genes and immunotherapy in osteoporosis patients.

Lei Wang, Chaosheng Deng, Zixuan Wu, Kaidong Zhu, Zhenguo Yang.

   BACKGROUND: Osteoporosis (OP), often referred to as the "silent disease of the twenty-first century," poses a significant public health concern due to its severity, chronic nature, and progressive course, predominantly affecting postmenopausal women and elderly individuals. The pathogenesis and progression of this disease have been associated with dysregulation in tumor metabolic pathways. Notably, the metabolic utilization of glutamine has emerged as a critical player in cancer biology. While metabolic reprogramming has been extensively studied in various malignancies and linked to clinical outcomes, its comprehensive investigation within the context of OP remains lacking.
METHODS: This study aimed to identify and validate potential glutamine metabolism genes (GlnMgs) associated with OP through comprehensive bioinformatics analysis. The identification of GlnMgs was achieved by integrating the weighted gene co-expression network analysis and a set of 28 candidate GlnMgs. Subsequently, the putative biological functions and pathways associated with GlnMgs were elucidated using gene set variation analysis. The LASSO method was employed to identify key hub genes, and the diagnostic efficacy of five selected GlnMgs in OP detection was assessed. Additionally, the relationship between hub GlnMgs and clinical characteristics was investigated. Finally, the expression levels of the five GlnMgs were validated using independent datasets (GSE2208, GSE7158, GSE56815, and GSE35956).
RESULTS: Five GlnMgs, namely IGKC, TMEM187, RPS11, IGLL3P, and GOLGA8N, were identified in this study. To gain insights into their biological functions, particular emphasis was placed on synaptic transmission GABAergic, inward rectifier potassium channel activity, and the cytoplasmic side of the lysosomal membrane. Furthermore, the diagnostic potential of these five GlnMgs in distinguishing individuals with OP yielded promising results, indicating their efficacy as discriminative markers for OP.
CONCLUSIONS: This study discovered five GlnMgs that are linked to OP. They shed light on potential new biomarkers for OP and tracking its progression.

Keywords:  Bioinformatics; DEGs; Gln-metabolism genes (GlnMgs); Osteoporosis (OP); WGCNA

DOI:  https://doi.org/10.1186/s13018-023-04152-2
Free Radic Biol Med. 2023 Sep 09. pii: S0891-5849(23)00624-X. [Epub ahead of print]

Canagliflozin reduces chemoresistance in hepatocellular carcinoma through PKM2-c-Myc complex-mediated glutamine starvation.

Yuan Zeng, Haoran Jiang, Xiangting Zhang, Jun Xu, Xiao Wu, Qian Xu, Weimin Cai, Huiya Ying, Ruoru Zhou, Yingrong Ding, Kanglei Ying, Xian Song, Zhuoyan Chen, Liuwei Zeng, Luying Zhao, Fujun Yu.

  Cisplatin (CPT) is one of the standard treatments for hepatocellular carcinoma (HCC). However, its use is limits as a monotherapy due to drug resistance, and the underlying mechanism remains unclear. To solve this problem, we tried using canagliflozin (CANA), a clinical drug for diabetes, to reduce chemoresistance to CPT, and the result showed that CANA could vigorously inhibit cell proliferation and migration independent of the original target SGLT2. Mechanistically, CANA reduced aerobic glycolysis in HCC by targeting PKM2. The downregulated PKM2 directly bound to the transcription factor c-Myc in the cytoplasm to form a complex, which upregulated the level of phosphorylated c-Myc Thr58 and promoted the ubiquitination and degradation of c-Myc. Decreased c-Myc reduced the expression of GLS1, a key enzyme in glutamine metabolism, leading to impaired glutamine utilization. Finally, intracellular glutamine starvation induced ferroptosis and sensitized HCC to CPT. In conclusion, our study showed that CANA re-sensitized HCC to CPT by inducing ferroptosis through dual effects on glycolysis and glutamine metabolism. This is a novel mechanism to increase chemosensitivity, which may provide compatible chemotherapy drugs for HCC.

Keywords:  Canagliflozin; GLS1; Glutamine; Glycolysis; Hepatocellular carcinoma

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.006
Signal Transduct Target Ther. 2023 Sep 13. 8(1): 345

Amino acid metabolism in health and disease.

Zhe-Nan Ling, Yi-Fan Jiang, Jun-Nan Ru, Jia-Hua Lu, Bo Ding, Jian Wu.

Amino acids are the building blocks of protein synthesis. They are structural elements and energy sources of cells necessary for normal cell growth, differentiation and function. Amino acid metabolism disorders have been linked with a number of pathological conditions, including metabolic diseases, cardiovascular diseases, immune diseases, and cancer. In the case of tumors, alterations in amino acid metabolism can be used not only as clinical indicators of cancer progression but also as therapeutic strategies. Since the growth and development of tumors depend on the intake of foreign amino acids, more and more studies have targeted the metabolism of tumor-related amino acids to selectively kill tumor cells. Furthermore, immune-related studies have confirmed that amino acid metabolism regulates the function of effector T cells and regulatory T cells, affecting the function of immune cells. Therefore, studying amino acid metabolism associated with disease and identifying targets in amino acid metabolic pathways may be helpful for disease treatment. This article mainly focuses on the research of amino acid metabolism in tumor-oriented diseases, and reviews the research and clinical research progress of metabolic diseases, cardiovascular diseases and immune-related diseases related to amino acid metabolism, in order to provide theoretical basis for targeted therapy of amino acid metabolism.

DOI: https://doi.org/10.1038/s41392-023-01569-3
Cell Chem Biol. 2023 Aug 31. pii: S2451-9456(23)00279-9. [Epub ahead of print]

Screening in serum-derived medium reveals differential response to compounds targeting metabolism.

Keene L Abbott, Ahmed Ali, Dominick Casalena, Brian T Do, Raphael Ferreira, Jaime H Cheah, Christian K Soule, Amy Deik, Tenzin Kunchok, Daniel R Schmidt, Steffen Renner, Sophie E Honeder, Michelle Wu, Sze Ham Chan, Tenzin Tseyang, Andrew T Stoltzfus, Sarah L J Michel, Daniel Greaves, Peggy P Hsu, Christopher W Ng, Chelsea J Zhang, Ali Farsidjani, Johnathan R Kent, Maria Lucia L Madariaga, Iva Monique T Gramatikov, Nicholas J Matheson, Caroline A Lewis, Clary B Clish, Matthew G Rees, Jennifer A Roth, Lesley Mathews Griner, Alexander Muir, Douglas S Auld, Matthew G Vander Heiden.

  A challenge for screening new anticancer drugs is that efficacy in cell culture models is not always predictive of efficacy in patients. One limitation of standard cell culture is a reliance on non-physiological nutrient levels, which can influence cell metabolism and drug sensitivity. A general assessment of how physiological nutrients affect cancer cell response to small molecule therapies is lacking. To address this, we developed a serum-derived culture medium that supports the proliferation of diverse cancer cell lines and is amenable to high-throughput screening. We screened several small molecule libraries and found that compounds targeting metabolic enzymes were differentially effective in standard compared to serum-derived medium. We exploited the differences in nutrient levels between each medium to understand why medium conditions affected the response of cells to some compounds, illustrating how this approach can be used to screen potential therapeutics and understand how their efficacy is modified by available nutrients.

Keywords:  Cancer cell metabolism; Culture media; Drug sensitivity; High-throughput screening; Nutrient environment; Phenotypic drug screening; Physiologic media

DOI:  https://doi.org/10.1016/j.chembiol.2023.08.007
J Transl Med. 2023 Sep 15. 21(1): 627

SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism.

Benluvankar Varghese, Ugo Chianese, Lucia Capasso, Veronica Sian, Paola Bontempo, Mariarosaria Conte, Rosaria Benedetti, Lucia Altucci, Vincenzo Carafa, Angela Nebbioso.

   BACKGROUND: Cancer cells are characterized by uncontrolled cell proliferation and impaired bioenergetics. Sirtuins are a family of highly conserved enzymes that play a fundamental role in energy metabolism regulation. SIRT1, in particular, drives many physiological stress responses and metabolic pathways following nutrient deprivation. We previously showed that SIRT1 activation using SCIC2.1 was able to attenuate genotoxic response and senescence. Here, we report that in hepatocellular carcinoma (HCC) cells under glucose-deprived conditions, SCIC2.1 treatment induced overexpression of SIRT1, SIRT3, and SIRT6, modulating metabolic response.
METHODS: Flow cytometry was used to analyze the cell cycle. The MTT assay and xCELLigence system were used to measure cell viability and proliferation. In vitro enzymatic assays were carried out as directed by the manufacturer, and the absorbance was measured with an automated Infinite M1000 reader. Western blotting and immunoprecipitation were used to evaluate the expression of various proteins described in this study. The relative expression of genes was studied using real-time PCR. We employed a Seahorse XF24 Analyzer to determine the metabolic state of the cells. Oil Red O staining was used to measure lipid accumulation.
RESULTS: SCIC2.1 significantly promoted mitochondrial biogenesis via the AMPK-p53-PGC1α pathway and enhanced mitochondrial ATP production under glucose deprivation. SIRT1 inhibition by Ex-527 further supported our hypothesis that metabolic effects are dependent on SIRT1 activation. Interestingly, SCIC2.1 reprogrammed glucose metabolism and fatty acid oxidation for bioenergetic circuits by repressing de novo lipogenesis. In addition, SCIC2.1-mediated SIRT1 activation strongly modulated antioxidant response through SIRT3 activation, and p53-dependent stress response via indirect recruitment of SIRT6.
CONCLUSION: Our results show that SCIC2.1 is able to promote energy homeostasis, attenuating metabolic stress under glucose deprivation via activation of SIRT1. These findings shed light on the metabolic action of SIRT1 in the pathogenesis of HCC and may help determine future therapies for this and, possibly, other metabolic diseases.

Keywords:  Energy metabolism; Liver cancer; PGC1α; SCIC2.1; SIRT1; Stress response

DOI:  https://doi.org/10.1186/s12967-023-04440-9
Cancer Sci. 2023 Sep 14.

Glutamine deficiency drives transforming growth factor-β signaling activation that gives rise to myofibroblastic carcinoma-associated fibroblasts.

Yoshihiro Mezawa, Tingwei Wang, Yataro Daigo, Atsushi Takano, Yohei Miyagi, Tomoyuki Yokose, Toshinari Yamashita, Liying Yang, Reo Maruyama, Hiroyuki Seimiya, Akira Orimo.

  Tumor-promoting carcinoma-associated fibroblasts (CAFs), abundant in the mammary tumor microenvironment (TME), maintain transforming growth factor-β (TGF-β)-Smad2/3 signaling activation and the myofibroblastic state, the hallmark of activated fibroblasts. How myofibroblastic CAFs (myCAFs) arise in the TME and which epigenetic and metabolic alterations underlie activated fibroblastic phenotypes remain, however, poorly understood. We herein show global histone deacetylation in myCAFs present in tumors to be significantly associated with poorer outcomes in breast cancer patients. As the TME is subject to glutamine (Gln) deficiency, human mammary fibroblasts (HMFs) were cultured in Gln-starved medium. Global histone deacetylation and TGF-β-Smad2/3 signaling activation are induced in these cells, largely mediated by class I histone deacetylase (HDAC) activity. Additionally, mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signaling is attenuated in Gln-starved HMFs, and mTORC1 inhibition in Gln-supplemented HMFs with rapamycin treatment boosts TGF-β-Smad2/3 signaling activation. These data indicate that mTORC1 suppression mediates TGF-β-Smad2/3 signaling activation in Gln-starved HMFs. Global histone deacetylation, class I HDAC activation, and mTORC1 suppression are also observed in cultured human breast CAFs. Class I HDAC inhibition or mTORC1 activation by high-dose Gln supplementation significantly attenuates TGF-β-Smad2/3 signaling and the myofibroblastic state in these cells. These data indicate class I HDAC activation and mTORC1 suppression to be required for maintenance of myCAF traits. Taken together, these findings indicate that Gln starvation triggers TGF-β signaling activation in HMFs through class I HDAC activity and mTORC1 suppression, presumably inducing myCAF conversion.

Keywords:  TGF-β/SMAD; class I HDAC; global histone deacetylation; glutamine starvation; mTORC1; myofibroblastic carcinoma-associated fibroblast

DOI:  https://doi.org/10.1111/cas.15955
Redox Biol. 2023 Sep 07. pii: S2213-2317(23)00279-3. [Epub ahead of print]67 102878

Sulforaphane rewires central metabolism to support antioxidant response and achieve glucose homeostasis.

Federico Bernuzzi, Andre Maertens, Shikha Saha, Perla Troncoso-Rey, Tobias Ludwig, Karsten Hiller, Richard F Mithen, Tamas Korcsmaros, Maria H Traka.

  Cruciferous-rich diets, particularly broccoli, have been associated with reduced risk of developing cancers of various sites, cardiovascular disease and type-2 diabetes. Sulforaphane (SF), a sulfur-containing broccoli-derived metabolite, has been identified as the major bioactive compound mediating these health benefits. Sulforaphane is a potent dietary activator of the transcription factor Nuclear factor erythroid-like 2 (NRF2), the master regulator of antioxidant cell capacity responsible for inducing cytoprotective genes, but its role in glucose homeostasis remains unclear. In this study, we set to test the hypothesis that SF regulates glucose metabolism and ameliorates glucose overload and its resulting oxidative stress by inducing NRF2 in human hepatoma HepG2 cells. HepG2 cells were exposed to varying glucose concentrations: basal (5.5 mM) and high glucose (25 mM), in the presence of physiological concentrations of SF (10 μM). SF upregulated the expression of glutathione (GSH) biosynthetic genes and significantly increased levels of reduced GSH. Labelled glucose and glutamine experiments to measure metabolic fluxes identified that SF increased intracellular utilisation of glycine and glutamate by redirecting the latter away from the TCA cycle and increased the import of cysteine from the media, likely to support glutathione synthesis. Furthermore, SF altered pathways generating NADPH, the necessary cofactor for oxidoreductase reactions, namely pentose phosphate pathway and 1C-metabolism, leading to the redirection of glucose away from glycolysis and towards PPP and of methionine towards methylation substrates. Finally, transcriptomic and targeted metabolomics LC-MS analysis of NRF2-KD HepG2 cells generated using CRISPR-Cas9 genome editing revealed that the above metabolic effects are mediated through NRF2. These results suggest that the antioxidant properties of cruciferous diets are intricately connected to their metabolic benefits.

Keywords:  CRISPR-Cas9; Glucose; Glutathione; Methionine; NADPH; NRF2; One-carbon (1C) metabolism; Pentose phosphate pathway; Sulforaphane

DOI:  https://doi.org/10.1016/j.redox.2023.102878
Bioeng Transl Med. 2023 Sep;8(5): e10470

Nanorod/nanodisk-integrated liquid crystalline systems for starvation, chemodynamic, and photothermal therapy of cancer.

Sungyun Kim, ChaeRim Hwang, Da In Jeong, JiHye Park, Han-Jun Kim, KangJu Lee, Junmin Lee, Seung-Hwan Lee, Hyun-Jong Cho.

  Indocyanine green (ICG), glucose oxidase (GOx), and copper(II) sulfate (Cu)-installed hybrid gel based on organic nanorod (cellulose nanocrystal [CNC]) and inorganic nanodisk (Laponite [LAP]) was developed to perform a combination of starvation therapy (ST), chemodynamic therapy (CDT), and photothermal therapy (PTT) for localized cancers. A hybrid CNC/LAP network with a nematic phase was designed to enable instant gelation, controlled viscoelasticity, syringe injectability, and longer in vivo retention. Moreover, ICG was introduced into the CNC/LAP gel system to induce hyperthermia of tumor tissue, amplifying the CDT effect; GOx was used for glucose deprivation (related to the Warburg effect); and Cu was introduced for hydroxyl radical generation (based on Fenton-like chemistry) and cellular glutathione (GSH) degradation in cancer cells. The ICG/GOx/Cu-installed CNC/LAP gel in combination with near-infrared (NIR) laser realized improved antiproliferation, cellular reactive oxygen species (ROS) generation, cellular GSH degradation, and apoptosis induction in colorectal cancer (CT-26) cells. In addition, local injection of the CNC/ICG/GOx/Cu/LAP gel into the implanted CT-26 tumor while irradiating it with NIR laser provided strong tumor growth suppression effects. In conclusion, the designed hybrid nanorod/nanodisk gel network can be efficiently applied to the local PTT/ST/CDT of cancer cells.

Keywords:  Laponite; cellulose nanocrystal; chemodynamic therapy; hybrid gel network; photothermal therapy

DOI:  https://doi.org/10.1002/btm2.10470
PLoS Comput Biol. 2023 Sep;19(9): e1011374

Mathematical reconstruction of the metabolic network in an in-vitro multiple myeloma model.

Elias Vera-Siguenza, Cristina Escribano-Gonzalez, Irene Serrano-Gonzalo, Kattri-Liis Eskla, Fabian Spill, Daniel Tennant.

It is increasingly apparent that cancer cells, in addition to remodelling their metabolism to survive and proliferate, adapt and manipulate the metabolism of other cells. This property may be a telling sign that pre-clinical tumour metabolism studies exclusively utilising in-vitro mono-culture models could prove to be limited for uncovering novel metabolic targets able to translate into clinical therapies. Although this is increasingly recognised, and work towards addressing the issue is becoming routinary much remains poorly understood. For instance, knowledge regarding the biochemical mechanisms through which cancer cells manipulate non-cancerous cell metabolism, and the subsequent impact on their survival and proliferation remains limited. Additionally, the variations in these processes across different cancer types and progression stages, and their implications for therapy, also remain largely unexplored. This study employs an interdisciplinary approach that leverages the predictive power of mathematical modelling to enrich experimental findings. We develop a functional multicellular in-silico model that facilitates the qualitative and quantitative analysis of the metabolic network spawned by an in-vitro co-culture model of bone marrow mesenchymal stem- and myeloma cell lines. To procure this model, we devised a bespoke human genome constraint-based reconstruction workflow that combines aspects from the legacy mCADRE & Metabotools algorithms, the novel redHuman algorithm, along with 13C-metabolic flux analysis. Our workflow transforms the latest human metabolic network matrix (Recon3D) into two cell-specific models coupled with a metabolic network spanning a shared growth medium. When cross-validating our in-silico model against the in-vitro model, we found that the in-silico model successfully reproduces vital metabolic behaviours of its in-vitro counterpart; results include cell growth predictions, respiration rates, as well as support for observations which suggest cross-shuttling of redox-active metabolites between cells.

DOI: https://doi.org/10.1371/journal.pcbi.1011374
Cancer Res. 2023 Sep 13.

CK1δ/CK1ε Signaling Sustains Mitochondrial Metabolism and Cell Survival in Multiple Myeloma.

Karen L Burger, Mario R Fernandez, Mark B Meads, Praneeth Reddy Sudalagunta, Paula S Oliveira, Rafael Renatino Canevarolo, Raghunandan Reddy Alugubelli, Alexandre Tungsevik, Gabe De Avila, Maria Silva, Allison I Graeter, Hongyue Dai, Nicole D Vincelette, Antony Prabhu, Dario Magaletti, Chunying Yang, Weimin Li, Amit Kulkarni, Oliver Alexander Hampton, John M Koomen, William R Roush, Andrii Monastyrskyi, Anders E Berglund, Ariosto S Silva, John L Cleveland, Kenneth H Shain.

Multiple myeloma (MM) remains an incurable malignancy due to acquisition of intrinsic programs that drive therapy resistance. Here we report that casein kinase-1δ (CK1δ) and CK1ε are therapeutic targets in MM that are necessary to sustain mitochondrial metabolism. Specifically, the dual CK1δ/CK1ε inhibitor SR-3029 had potent in vivo and ex vivo anti-MM activity, including against primary MM patient specimens. RNA sequencing (RNA-seq) and metabolic analyses revealed inhibiting CK1δ/CK1ε disables MM metabolism by suppressing genes involved in oxidative phosphorylation (OxPhos), reducing citric acid cycle intermediates, and suppressing Complexes I and IV of the electron transport chain. Finally, sensitivity of MM patient specimens to SR-3029 correlated with elevated expression of mitochondrial genes, and RNA-seq from 687 MM patient samples revealed that increased CSNK1D, CSNK1E, and OxPhos genes correlates with disease progression and inferior outcomes. Thus, increases in mitochondrial metabolism are a hallmark of MM progression that can be disabled by targeting CK1δ/CK1ε.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2350
Angew Chem Int Ed Engl. 2023 Sep 09. e202308909

Crosstalk between hepatic glutathione efflux and tumor targeting of ICG-conjugated gold nanoparticles.

Yingyu Huang, Wei Xiao, Samira Ahrari, Mengxiao Yu, Jie Zheng.

  The elevated glutathione (GSH) level in solid tumors has been used as a major hallmark for GSH-responsive nanoparticles to enhance targeting efficiency and specificity. Meanwhile, GSH is mainly synthesized inside the hepatocytes of the liver in the body and constantly released into the blood through hepatic GSH efflux to regulate redox potential of the entire body. However, it remains largely unknown how the liver crosses talk with tumor in the nanoparticle targeting through hepatic GSH efflux. Herein, we report that depletion of hepatic GSH enhanced the tumor targeting of GSH-responsive indocyanine green-conjugated Au25 nanoclusters coated with 18 GSH ligand (ICG-Au25SG18). The dissociation of ICG from Au25SG18 by the hepatic GSH through thiol-exchange reaction and the subsequent hepatobiliary clearance of the detached ICG were slowed down by GSH depletion, which in turn prolonged the blood circulation of intact ICG-Au25SG18 and enhanced its tumor targeting. Our work highlights glutathione-mediated crosstalk between the liver and tumor, in addition to well-known Kupffer cell-mediated uptake, in the tumor targeting of engineered nanoparticles, which could be modulated to enhance targeting efficiency and specificity of cancer nanomedicines while reducing their nonspecific accumulation.

Keywords:  Nano-biochemical interactions, the liver, biotransformation, glutathione, cancer, renal clearable nanoparticles

DOI:  https://doi.org/10.1002/anie.202308909
Cancer Biol Ther. 2023 Dec 31. 24(1): 2255369

A study on metabolic characteristics and metabolic markers of gastrointestinal tumors.

Shan Cong, Shanshan Bai, Minghao Zhang, Yanfang Bi, Yu Wang, Shi Jin, Hui He.

  Tumor cells have significant heterogeneity in metabolism and are closely related to prognosis, gene mutation, and subtype. However, this association has not been demonstrated in reports of gastrointestinal tumors. In this study, we constructed four metabolic subtypes and identified four gene signatures using the expression data and clinical information of 252 metabolism-related genes from TCGA and NCBI databases for gastric adenocarcinoma (STAD) and colorectal cancer (COAD and READ). MC1 had the worst prognosis compared to other classifications. GSig1 was mainly related to drug metabolism and was the highest in MC1 with the worst prognosis, while the other subtypes were mainly related to glucose metabolism pathways. This difference also existed in other different malignant tumors. In addition, metabolic typing was associated with chemotherapeutic drug response and tumor heterogeneity, which indicated that monitoring metabolic typing could contribute to drug efficacy and gene-targeted therapy. In conclusion, we identified differences among subtypes in clinical characteristics such as prognosis and revealed the potential function of metabolic subtype in response to chemotherapeutic agents and oncogene mutations. This work highlighted the potential clinical meaning of metabolic subtype and characteristics in drug therapy and prognosis assessment of malignant tumors.

Keywords:  Gastrointestinal tumor; TCGA database; drug response; metabolic subtype; prognosis

DOI:  https://doi.org/10.1080/15384047.2023.2255369
Br J Cancer. 2023 Sep 09.

Fumarate hydratase (FH) and cancer: a paradigm of oncometabolism.

Lorea Valcarcel-Jimenez, Christian Frezza.

Fumarate hydratase (FH) is an enzyme of the Tricarboxylic Acid (TCA) cycle whose mutations lead to hereditary and sporadic forms of cancer. Although more than twenty years have passed since its discovery as the leading cause of the cancer syndrome Hereditary leiomyomatosis and Renal Cell Carcinoma (HLRCC), it is still unclear how the loss of FH causes cancer in a tissue-specific manner and with such aggressive behaviour. It has been shown that FH loss, via the accumulation of FH substrate fumarate, activates a series of oncogenic cascades whose contribution to transformation is still under investigation. In this review, we will summarise these recent findings in an integrated fashion and put forward the case that understanding the biology of FH and how its mutations promote transformation will be vital to establish novel paradigms of oncometabolism.

DOI: https://doi.org/10.1038/s41416-023-02412-w
Int J Cancer. 2023 Sep 12.

Removal of gemcitabine-induced senescent cancer cells by targeting glutaminase1 improves the therapeutic effect in pancreatic ductal adenocarcinoma.

Keisuke Oyama, Yoshifumi Iwagami, Shogo Kobayashi, Kazuki Sasaki, Daisaku Yamada, Yoshito Tomimaru, Takehiro Noda, Tadafumi Asaoka, Hidenori Takahashi, Masahiro Tanemura, Yuichiro Doki, Hidetoshi Eguchi.

  Insufficient cancer treatment can induce senescent cancer cell formation and treatment resistance. The characteristics of induced senescent cancer (iSnCa) cells remain unclear. Pancreatic ductal adenocarcinoma (PDAC) has a low and nondurable response rate to current treatments. Our study aimed to analyze the properties of iSnCa cells and the relationship between cellular senescence and prognosis in PDAC. We evaluated the characteristics of gemcitabine-induced senescent cancer cells and the effect of senescence-associated secretory phenotype (SASP) factors released by iSnCa cells on surrounding PDAC cells. The relationship between cellular senescence and the prognosis was investigated in 50 patients with PDAC treated with gemcitabine-based neoadjuvant chemotherapy. Exposure to 5 ng/mL gemcitabine-induced senescence, decreased proliferation and increased senescence-associated β-galactosidase-cell staining without cell death in PDAC cells; the expression of glutaminase1 (GLS1) and SASP factors also increased and caused epithelial-mesenchymal transition in surrounding PDAC cells. iSnCa cells were selectively removed by the GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) through apoptosis induction. Cellular senescence was induced in PDAC cells via insufficient gemcitabine in subcutaneous tumor model mice. GLS1 expression was an independent prognostic factor in patients with PDAC who received gemcitabine-based neoadjuvant chemotherapy. This is the first study to identify the relationship between senescence and GLS1 in PDAC. Low-dose gemcitabine-induced senescence and increased GLS1 expression were observed in PDAC cells. Cellular senescence may contribute to treatment resistance of PDAC, hence targeting GLS1 in iSnCa cells may improve the therapeutic effect.

Keywords:  gemcitabine; glutaminase1; induced senescent cancer cell; pancreatic ductal adenocarcinoma; senescence

DOI:  https://doi.org/10.1002/ijc.34725