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1
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Tan SM, Luo L, He YF, Li W, Wan XX. Daurisoline inhibits glycolysis of lung cancer by targeting the AKT-HK2 axis. Cancer Biol Ther 2025; 26:2442556. [PMID: 39699276 DOI: 10.1080/15384047.2024.2442556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 12/08/2024] [Accepted: 12/11/2024] [Indexed: 12/20/2024] Open
Abstract
Lung cancer, one of the most prevalent tumors, remains a clinical challenge with a poor five-year survival rate. Daurisoline, a bis-benzylisoquinoline alkaloid derived from the traditional Chinese herb Menispermum dauricum, is known to suppress tumor growth effectively. However, its precise mechanism of action remains unclear. In this study, we demonstrate that Daurisoline targets glycolysis and reduces the protein level of HK2, thereby inhibiting lung cancer progression. Mechanistic investigations reveal that Daurisoline directly binds to AKT and antagonizes the AKT-GSK3β-c-Myc-HK2 signaling axis. Furthermore, in an animal model, we validate the in vivo anti-tumor effect of Daurisoline without any observable side effects. Overall, our findings suggest that Daurisoline holds potential as an anti-tumor agent through its targeting of glycolysis.
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Affiliation(s)
- Shi-Ming Tan
- Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Lan Luo
- Department of Obstetrics and Gynecology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yi-Fu He
- Department of Obstetrics and Gynecology, Xiangya Hospital, Central South University, Changsha, China
| | - Wei Li
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xin-Xing Wan
- Department of Endocrinology, The Third Xiangya Hospital, Central South University, Changsha, China
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2
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Zhu G, Ruan Q, Tian Z, Liu F, Guo L, Zhang Z. Chitosan-based fluorescent nanocarriers: A novel drug delivery strategy for oral squamous cell carcinoma therapy. Carbohydr Res 2025; 552:109459. [PMID: 40106912 DOI: 10.1016/j.carres.2025.109459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 03/07/2025] [Accepted: 03/11/2025] [Indexed: 03/22/2025]
Abstract
Oral squamous cell carcinoma (OSCC) accounts for over 90 % of all oral cancers, underscoring the urgent need for effective treatment strategies to improve patient survival. Grape seed polyphenols (GSP), a naturally occurring plant-derived compound, have shown promise as a therapeutic agent for OSCC. However, their clinical application is limited by poor solubility and instability. To address these challenges, coordination polymers (CPs) were employed as drug carriers, enhancing GSP's solubility, bioavailability, and controlled release. In this study, compound 1 (CP1) was synthesized and incorporated with GSP (CP1@1@GSP), significantly improving drug encapsulation efficiency (over 50 %) and drug loading (16 %), ensuring more effective drug delivery. Despite these advantages, concerns about metal ion release and potential immune responses necessitate further safety evaluation. To mitigate these risks, chitosan (CS), a biocompatible and low-toxicity natural polymer, was introduced. The development of pyrene-modified chitosan-based hollow nanoparticles (Pyrene-CS@CP1@1@GSP) facilitated both drug delivery and fluorescence-based real-time tracking. Characterization using scanning electron microscopy (SEM) and dynamic light scattering (DLS) confirmed the uniform spherical morphology of the nanoparticles, with an average size of approximately 150 nm, stable dispersion, a low polydispersity index (PDI), and excellent self-assembly properties. Further functional evaluation revealed that Pyrene-CS@CP1@1@GSP effectively modulates glycolysis in OSCC cells. Treatment significantly inhibited OSCC cell proliferation in a dose-dependent manner, with glucose levels in the cell supernatant increasing significantly (p < 0.05), indicating reduced glucose uptake by cancer cells. Simultaneously, lactic acid levels decreased (p < 0.05), suggesting suppression of glycolytic activity. Additionally, fluorescence quenching and subsequent restoration of pyrene fluorescence during drug release enabled real-time tracking of drug distribution. These findings demonstrate that Pyrene-CS@CP1@1@GSP enhances the bioavailability and stability of GSP while effectively regulating glycolysis, thereby influencing OSCC progression. This study presents a promising strategy for targeted OSCC therapy, offering both improved treatment efficacy and real-time drug release monitoring, with potential applications in future clinical settings.
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Affiliation(s)
- Gang Zhu
- College of Agriculture and Bioengineering, Heze University, Heze, 274000, China
| | - Qiang Ruan
- Department of Stomatology, Heze Municipal Hospital, Heze, 274000, China
| | - Zhonghui Tian
- Department of Stomatology, Heze Municipal Hospital, Heze, 274000, China
| | - Fengxia Liu
- Department of Stomatology, Heze Municipal Hospital, Heze, 274000, China
| | - Luyan Guo
- Department of Stomatology, Heze Municipal Hospital, Heze, 274000, China
| | - Zhongrui Zhang
- Department of Stomatology, Heze Municipal Hospital, Heze, 274000, China.
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3
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Shen R, Xia P, Guo Y, Ji P, Yuan X, Wang L, Shuang S, Zhou L, Tong R, Zhang L, Liu D, Wang D. Effects of polystyrene microparticles exposures on spermatogenic cell differentiation and reproductive endpoints in male mice. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2025; 373:126200. [PMID: 40185193 DOI: 10.1016/j.envpol.2025.126200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 03/27/2025] [Accepted: 04/02/2025] [Indexed: 04/07/2025]
Abstract
The widespread distribution of microplastics in the environment has raised concerns about their potential implications for human health. Microplastics accumulate in animals and humans, but the risks associated with these pollutants are not fully understood. This study aimed to investigate the effects of polystyrene microplastics on the male reproductive system. The 0.1 μm polystyrene (PS) could accumulate in the testicular tissue and spermatogonia GC-1, while 1 μm PS was not easy to enter and accumulate in the testicular tissue and cells. Mice continuously exposed for 3-months to 0.1 μm PS demonstrated lower fertility and inhibited spermatogonium differentiation compared to control mice. The 0.1 μm PS were dispersed throughout the seminiferous tubule of the testis. Metabolic reprogramming was found to be involved in these processes. Histone methylation and autophagy-related pathways showed significant differences following PS treatment in testis tissue and GC-1 cells. Our findings suggest that chronic exposure to 0.1 μm PS inhibited spermatogenic cell differentiation and impaired fertility in male mice. We propose that abnormal epigenetic modifications in 0.1 μm PS exposed mice contributed to the dysregulation of glycolytic enzymes, and that the impaired autophagic pathway exacerbated the accumulation of glycolytic enzymes further. Glycolysis plays a critical role in the regulation of spermatogenic cell differentiation, and its regulation partially alleviated the impairments associated with PS exposure. In conclusion, our findings suggest that chronic exposure to nanoplastics PS inhibited spermatogenic cell differentiation and impaired fertility in male mice via disrupted epigenetic modification and metabolic dysregulation.
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Affiliation(s)
- Rong Shen
- School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China
| | - Peng Xia
- School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China
| | - Yanan Guo
- School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China
| | - Pengfei Ji
- School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China
| | - Xinyi Yuan
- School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China
| | - Lu Wang
- The First Hospital of Lanzhou University, Lanzhou University, Gansu, 730000, China
| | - Si Shuang
- School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China
| | - Liwei Zhou
- School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China
| | - Ruizhi Tong
- The First Hospital of Lanzhou University, Lanzhou University, Gansu, 730000, China
| | - Lijuan Zhang
- Medical Experimental Center, Lanzhou University, Gansu, 730000, China
| | - Disheng Liu
- The First Hospital of Lanzhou University, Lanzhou University, Gansu, 730000, China.
| | - Degui Wang
- School of Basic Medical Sciences, Lanzhou University, Gansu, 730000, China.
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4
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Feng Y, Lu Y. The nuclear-mitochondrial crosstalk in aging: From mechanisms to therapeutics. Free Radic Biol Med 2025; 232:391-397. [PMID: 40086490 DOI: 10.1016/j.freeradbiomed.2025.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 02/28/2025] [Accepted: 03/11/2025] [Indexed: 03/16/2025]
Abstract
Aging is a complex physiological process characterized by an irreversible decline in tissue and cellular functions, accompanied by an increased risk of age-related diseases, including neurodegenerative, cardiovascular, and metabolic disorders. Central to this process are epigenetic modifications, particularly DNA methylation, which regulate gene expression and contribute to aging-related epigenetic drift. This drift is characterized by global hypomethylation and localized hypermethylation, impacting genomic stability and cellular homeostasis. Simultaneously, mitochondrial dysfunction, a hallmark of aging, manifests as impaired oxidative phosphorylation, excessive reactive oxygen species production, and mitochondrial DNA mutations, driving oxidative stress and cellular senescence. Emerging evidence highlights a bidirectional interplay between epigenetics and mitochondrial function. DNA methylation modulates the expression of nuclear genes governing mitochondrial biogenesis and quality control, while mitochondrial metabolites, such as acetyl-CoA and S-adenosylmethionine, reciprocally influence epigenetic landscapes. This review delves into the intricate nuclear-mitochondrial crosstalk, emphasizing its role in aging-related diseases and exploring therapeutic avenues targeting these interconnected pathways to counteract aging and promote health span extension.
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Affiliation(s)
- Yifei Feng
- Department of Dermatology, Jiangsu Province Hospital, The First Affiliated Hospital with Nanjing Medical University, Nanjing, PR China
| | - Yan Lu
- Department of Dermatology, Jiangsu Province Hospital, The First Affiliated Hospital with Nanjing Medical University, Nanjing, PR China.
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5
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Song N, Ji E, Yu JE, Choi KH, Kim DH, Song JM, Kang DH, Song JK, Yu J, Kim K, Lee S, Aikawa E. Spermidine Enhances Mitochondrial Function and Mitigates Aortic Valve Calcification: Implications for DNA Methyltransferase-1 Activity. JACC Basic Transl Sci 2025; 10:345-366. [PMID: 40139876 PMCID: PMC12013848 DOI: 10.1016/j.jacbts.2024.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 03/29/2025]
Abstract
Aortic stenosis (AS) is a severe heart valve disease marked by calcification, leading to heart failure. This study examined mitochondrial function in human aortic valve interstitial cells isolated from patients with AS and tested spermidine, an autophagy inducer as AS treatment. Spermidine treatment reduced fibrosis and calcification in human aortic valve interstitial cells and improved these features in spermidine-treated mice. The AKT-TP53-DNMT1-PPARG pathway was implicated, and DNA methyltransferase 1 inhibition by 5-azacytidine enhanced mitochondrial biogenesis by reducing mitochondrial DNA hypermethylation. These findings suggest that spermidine or DNA methyltransferase 1 inhibition could prevent aortic valve disease by improving mitochondrial function.
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Affiliation(s)
- Naaleum Song
- Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eunhye Ji
- Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeong Eun Yu
- Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyoung-Hee Choi
- Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dae-Hee Kim
- Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jong-Min Song
- Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Duk-Hyun Kang
- Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae-Kwan Song
- Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jiyoung Yu
- Convergence Medicine Research Center, Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Kyunggon Kim
- Convergence Medicine Research Center, Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea; Department of Digital Medicine, Brain Korea 21 plus, University of Ulsan College of Medicine and Department of Convergence Medicine and Asan Institute of Life Science, Asan Medical Center, Seoul, Republic of Korea
| | - Sahmin Lee
- Division of Cardiology, Heart Institute, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Elena Aikawa
- Department of Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
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6
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Zhu H, Xie Z. Therapeutic potential of tLyp-1-EV-shCTCF in inhibiting liver cancer stem cell self-renewal and immune escape via SALL3 modulation in hepatocellular carcinoma. Transl Oncol 2024; 49:102048. [PMID: 39186862 PMCID: PMC11388803 DOI: 10.1016/j.tranon.2024.102048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 06/12/2024] [Accepted: 07/01/2024] [Indexed: 08/28/2024] Open
Abstract
The progression of hepatocellular carcinoma (HCC) is influenced by disrupted metabolic processes, presenting challenges in prognostic outcomes. Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality, is closely associated with metabolic reprogramming and stem cell-like properties in liver cancer stem cells (LCSCs). This study explored the potential molecular mechanisms by which tLyP-1-modified extracellular vesicles (EVs) delivering CTCF shRNA (tLyp-1-EV-shCTCF) regulate mitochondrial DNA methylation-induced glycolytic metabolic reprogramming and LCSC self-renewal. Through a series of methods, including Western blot, nanoparticle tracking analysis, and immunofluorescence, we demonstrated the successful delivery and internalization of tLyp-1-EV in HCC cells. Our results identified SALL3 as a critical factor underexpressed in HCC and LCSCs, while CTCF was overexpressed. Overexpression of SALL3 inhibited LCSC self-renewal and immune evasion by blocking the CTCF-DNMT3A interaction, thus repressing DNMT3A methyltransferase activity and subsequent mitochondrial DNA methylation-mediated glycolytic metabolic reprogramming. In vivo experiments further supported these findings, showing that tLyp-1-EV-shCTCF treatment significantly reduced tumor growth by upregulating SALL3 expression, thereby inhibiting glycolytic metabolic reprogramming and enhancing the immune response against HCC cells. This study provides novel insights into the role of SALL3 and mitochondrial DNA methylation in HCC progression, offering potential therapeutic targets for combating HCC and its stem cell-like properties.
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Affiliation(s)
- Heng Zhu
- Department of Gastroenterology, The Fourth People's Hospital of Jinan, No.50, Normal Road, Tianqiao District, Jinan, Shandong Province 250031, P R China.
| | - Zhihui Xie
- Department of infectious diseases, Zibo Central Hospital, Zibo 255000, P R China
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7
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Cameron M, Frame F, Maitland NJ, Hancock Y. Raman spectroscopy reveals oxidative stress-induced metabolic vulnerabilities in early-stage AR-negative prostate-cancer versus normal-prostate cell lines. Sci Rep 2024; 14:25388. [PMID: 39455589 PMCID: PMC11512068 DOI: 10.1038/s41598-024-70338-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 08/14/2024] [Indexed: 10/28/2024] Open
Abstract
Quantitative Raman spectroscopy provides information-rich imaging of complex tissues. To illustrate its ability to characterise early-stage disease, we compared live P4E6, a low-grade Gleason-3 prostate-cancer cell line, to PNT2-C2, a normal prostate cell-line equivalent, thereby elucidating key molecular and mechanistic differences. Spectral changes from statistically relevant population sampling show P4E6 is defined by reduced DNA/RNA signatures (primarily base-pair modifications), increased protein-related signatures (synthesis), decreased whole-cell measured saturated and unsaturated fatty acids, and increased cholesterol and cholesterol ester (lipid storage). Signatures in the live-cell disease state point to the Warburg effect for aerobic glycolysis as the mechanism for cellular energy generation. A follow-on study involving catastrophic desiccation showed a key survival pathway in the cancer state in the structural robustness of DNA/RNA. Metabolic changes, namely in Warburg-to-oxidative-phosphorylation rerouting and reduced protein synthesis, were also shown. Such modifications limit cancer's resistance to oxidative damage, and thus its ability to utilise a higher redox homeostasis for metabolic advantage. The results demonstrate the ability of quantitative Raman spectroscopy to uncover, with full molecular-heterogeneity capture, mechanistic vulnerabilities in lowest-grade tumorigenic prostate cancer, thereby revealing underlying targets for disease disruption at early stage.
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Affiliation(s)
- M Cameron
- School of Physics, Engineering and Technology, University of York, Heslington, York, YO10 5DD, UK
| | - F Frame
- Department of Biology, University of York, Heslington, York, YO10 5DD, UK
- York Biomedical Research Institute, University of York, Heslington, York, YO10 5DD, UK
| | - N J Maitland
- Department of Biology, University of York, Heslington, York, YO10 5DD, UK
- York Biomedical Research Institute, University of York, Heslington, York, YO10 5DD, UK
| | - Y Hancock
- School of Physics, Engineering and Technology, University of York, Heslington, York, YO10 5DD, UK.
- York Biomedical Research Institute, University of York, Heslington, York, YO10 5DD, UK.
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8
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Nicolini A, Ferrari P. Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy. Front Immunol 2024; 15:1353787. [PMID: 39119332 PMCID: PMC11306065 DOI: 10.3389/fimmu.2024.1353787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 03/04/2024] [Indexed: 08/10/2024] Open
Abstract
Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)-one of the most prevalent cancers-has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.
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Affiliation(s)
- Andrea Nicolini
- Department of Oncology, Transplantations and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Paola Ferrari
- Unit of Oncology, Department of Medical and Oncological Area, Azienda Ospedaliera-Universitaria Pisana, Pisa, Italy
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9
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Chen J, He G, Cai D, Giovannetti E, Inamura K, Liu S, Ma W. Lactic acid: a narrative review of a promoter of the liver cancer microenvironment. J Gastrointest Oncol 2024; 15:1282-1296. [PMID: 38989406 PMCID: PMC11231854 DOI: 10.21037/jgo-24-368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 05/30/2024] [Indexed: 07/12/2024] Open
Abstract
Background and Objective Lactic acid is a metabolite of glycolysis produced in the body, and its production is thought to be a mechanism by which cancer cells evade immune surveillance. Immune evasion and metabolic changes are well established as basic hallmarks of cancer. Although lactate has long been considered a waste product, it is now generally recognized to be a versatile small-molecule chemical that plays an important part in the tumor microenvironment (TME), with increased lactate production linked to the development of human malignancies. Metabolism in liver cancer is redirected toward glycolysis, which enhances the production of metabolic compounds used by tumor cells to produce proteins, lipids, and nucleotides, enabling them to maintain high proliferation rates and to establish the TME. Dysregulation of metabolic activity in liver cancer may impair antitumor responses owing to the immunosuppressive activity of the lactate produced by anaerobic glycolytic rates in tumor cells. This review primarily explores the link connection between lactic acid and the TME; evaluates the role of lactic acid in the occurrence, metastasis, prognosis, and treatment of liver cancer. Additionally, it investigates the associated pathways as potential targets for liver cancer treatment. Methods Literature searches were conducted in PubMed, Web of Science, and Google Scholar, with the publication date of the most recent article included being January 2024. After eliminating duplicate articles and less relevant articles through titles and abstracts, we selected 113 articles for this review. We categorized references into two categories. One is to classify the content into lactate-related, liver cancer-related and tumor metabolism-related. The other is to classify the article types, which are divided into reviews, research articles and clinical trials. Additionally, we consulted the reference lists of the relevant articles to ensure coverage was comprehensive and unbiased. Key Content and Findings The connection between lactic acid and the TME has recently become an area of intense research interest, and many related articles have been published in this field. The main finding of this review is to summarize the proven link between lactate and the TME and its possible impact on the TME of liver cancer. And analyzed the potential of lactate in liver cancer treatment and prognosis prediction. Conclusions Lactate may be key to developing novel approaches in the future treatment of liver cancer. Related research on the combination of classic therapies and molecular targeted drugs may provide innovative medicines that more selectively regulate immune cell activity.
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Affiliation(s)
- Junhe Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Guifang He
- Medical Research Center, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Duo Cai
- Medical Research Center, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Elisa Giovannetti
- Department of Medical Oncology, Amsterdam University Medical Center, VU University, Amsterdam, The Netherlands
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisana per la Scienza, San Giuliano Terme, Italy
| | - Kentaro Inamura
- Department of Pathology, Jichi Medical University, Tochigi, Japan
- Division of Pathology, Cancer Institute of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shihai Liu
- Medical Research Center, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Wenzhe Ma
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
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10
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Avila-Barnard S, Ha M, Nemarugommula C, Wiegand JL, Ke H, De Souza A, Behar R, Volz DC. Tris(1,3-dichloro-2-propyl) phosphate disrupts cellular metabolism within human embryonic kidney (HEK293) cells. JOURNAL OF HAZARDOUS MATERIALS 2024; 466:133660. [PMID: 38309160 PMCID: PMC10923128 DOI: 10.1016/j.jhazmat.2024.133660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/12/2023] [Accepted: 01/27/2024] [Indexed: 02/05/2024]
Abstract
Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is a widely used, additive flame retardant that migrates from end-use products, leading to ubiquitous exposure of humans around the world. However, little is known about whether TDCIPP disrupts the physiology of human embryonic cells. Therefore, the objective of this study was to determine whether TDCIPP alters cell viability, cellular metabolism, cytosine methylation, and reactive oxygen species (ROS) levels within human embryonic kidney (HEK293) cells. Relative to vehicle controls, TDCIPP (0.015-0.1225 µM) resulted in a concentration-dependent increase in cell viability, a finding that was driven by an increase in relative ATP abundance. Interestingly, TDCIPP (0.061-0.98 µM) increased the rate of glycolysis - an adaptive mechanism consistent with the Warburg effect exhibited by tumorigenic cells. Moreover, relative to vehicle-treated cells, TDCIPP (0.245-15.63 µM) exposure for 48 h (but not 24 h) resulted in a significant, concentration-dependent decrease in ROS in situ, and TDCIPP (0.245 µM) exposure significantly increased carnosine within the histidine metabolism pathway. However, TDCIPP did not affect global 5-methylcytosine (5-mC) methylation (0.015-15.63 µM), cell membrane integrity (0.061-0.98 µM), nor the abundance of mitochondria (0.061-1.95 µM). Overall, our findings with TDCIPP point to a novel mechanism of action that may be relevant to human embryonic stem cells.
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Affiliation(s)
- Sarah Avila-Barnard
- Department of Environmental Sciences, University of California, Riverside, CA 92521, USA
| | - Megan Ha
- Department of Environmental Sciences, University of California, Riverside, CA 92521, USA
| | - Charvita Nemarugommula
- Department of Environmental Sciences, University of California, Riverside, CA 92521, USA
| | - Jenna L Wiegand
- Department of Environmental Sciences, University of California, Riverside, CA 92521, USA
| | - Haiyan Ke
- Metabolomics Core Facility, Institute for Integrative Genome Biology, University of California, Riverside, CA, USA
| | - Amancio De Souza
- Metabolomics Core Facility, Institute for Integrative Genome Biology, University of California, Riverside, CA, USA
| | - Rachel Behar
- Stem Cell Core Facility, University of California, Riverside, CA, USA
| | - David C Volz
- Department of Environmental Sciences, University of California, Riverside, CA 92521, USA.
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11
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Flood D, Lee ES, Taylor CT. Intracellular energy production and distribution in hypoxia. J Biol Chem 2023; 299:105103. [PMID: 37507013 PMCID: PMC10480318 DOI: 10.1016/j.jbc.2023.105103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
The hydrolysis of ATP is the primary source of metabolic energy for eukaryotic cells. Under physiological conditions, cells generally produce more than sufficient levels of ATP to fuel the active biological processes necessary to maintain homeostasis. However, mechanisms underpinning the distribution of ATP to subcellular microenvironments with high local demand remain poorly understood. Intracellular distribution of ATP in normal physiological conditions has been proposed to rely on passive diffusion across concentration gradients generated by ATP producing systems such as the mitochondria and the glycolytic pathway. However, subcellular microenvironments can develop with ATP deficiency due to increases in local ATP consumption. Alternatively, ATP production can be reduced during bioenergetic stress during hypoxia. Mammalian cells therefore need to have the capacity to alter their metabolism and energy distribution strategies to compensate for local ATP deficits while also controlling ATP production. It is highly likely that satisfying the bioenergetic requirements of the cell involves the regulated distribution of ATP producing systems to areas of high ATP demand within the cell. Recently, the distribution (both spatially and temporally) of ATP-producing systems has become an area of intense investigation. Here, we review what is known (and unknown) about intracellular energy production and distribution and explore potential mechanisms through which this targeted distribution can be altered in hypoxia, with the aim of stimulating investigation in this important, yet poorly understood field of research.
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Affiliation(s)
- Darragh Flood
- Conway Institute of Biomolecular and Biomedical Research and School of Medicine, University College Dublin, Dublin, Ireland
| | - Eun Sang Lee
- Conway Institute of Biomolecular and Biomedical Research and School of Medicine, University College Dublin, Dublin, Ireland
| | - Cormac T Taylor
- Conway Institute of Biomolecular and Biomedical Research and School of Medicine, University College Dublin, Dublin, Ireland.
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12
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Chu YD, Chen CW, Lai MW, Lim SN, Lin WR. Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly. World J Gastroenterol 2023; 29:4499-4527. [PMID: 37621758 PMCID: PMC10445009 DOI: 10.3748/wjg.v29.i29.4499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/23/2023] [Accepted: 07/03/2023] [Indexed: 08/02/2023] Open
Abstract
Cancer cells exhibit metabolic reprogramming and bioenergetic alteration, utilizing glucose fermentation for energy production, known as the Warburg effect. However, there are a lack of comprehensive reviews summarizing the metabolic reprogramming, bioenergetic alteration, and their oncogenetic links in gastrointestinal (GI) cancers. Furthermore, the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation. This review highlights the interplay between aerobic glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) in cancer cells, as well as hypotheses on the molecular mechanisms that trigger this alteration. The role of hypoxia-inducible transcription factors, tumor suppressors, and the oncogenetic link between hypoxia-related enzymes, bioenergetic changes, and GI cancer are also discussed. This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy, particularly for GI cancers. Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy, the review categorizes these regulators into aerobic glycolysis/ lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS. We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers, as well as the challenges posed by these drugs. Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments, although the diverse metabolic patterns present challenges for targeted therapies. Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes, address side effects, and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.
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Affiliation(s)
- Yu-De Chu
- Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Chun-Wei Chen
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Wei Lai
- Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Siew-Na Lim
- Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Wey-Ran Lin
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- Department of Medicine, Chang Gung University, Taoyuan 333, Taiwan
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13
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Cai J, Shen W, Zhang G, Li X, Shen H, Li W, Tan C, Zhang T, Shi M, Yang Z, Li Y, Liu H, Zhao X. Xiao Chai Hu Tang alleviates the pancreatic tumorigenesis via improving the mtDNA N6-Methyladenine modification mediated mitochondrial dysfunction in Syrian hamster model. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 116:154840. [PMID: 37172477 DOI: 10.1016/j.phymed.2023.154840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 03/24/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023]
Abstract
BACKGROUND Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion of pancreatic ductal adenocarcinoma (PDAC), which is a highly malignant tumor and lack of effective treatment. Although Xiao Chai Hu Tang (XCHT) has a good therapeutic effect on pancreatic cancer patients with advanced stage, the effect and mechanism of XCHT remains unclear in pancreatic tumorigenesis. PURPOSE To assess the therapeutic effects of XCHT on the malignant transformation from PanIN to PDAC and to reveal its mechanisms of pancreatic tumorigenesis. METHODS Syrian golden hamster were induced by N-Nitrosobis (2-oxopropyl) amine (BOP) to establish the pancreatic tumorigenesis model. The morphological changes of pancreatic tissue were observed by H&E and Masson staining; the Gene ontology (GO) analysis the transcriptional profiling changes; the mitochondrial ATP generation, mitochondrial redox status, mitochondrial DNA (mtDNA) N6-methyladenine (6mA) level and relative mtDNA genes expressions were examined. In addition, immunofluorescence detect the cell localization of 6mA in human pancreatic cancer PANC1 cell. Using the TCGA database, the prognostic effect of mtDNA 6mA demethylation ALKBH1 expression on pancreatic cancer patients was analyzed. RESULTS We confirmed the mtDNA 6mA levels were gradually increased with the mitochondrial dysfunction in PanINs progression. XCHT showed the effect to inhibit the occurrence and development of pancreatic cancer in Syrian hamster pancreatic tumorigenesis model. In addition, the lack of ALKBH1 mediated mtDNA 6mA increase, mtDNA coded genes down-expression and abnormal redox status were rescued by XCHT. CONCLUSIONS ALKBH1/mtDNA 6mA mediated mitochondrial dysfunction to induce the occurrence and progression of pancreatic cancer. XCHT can improve ALKBH1 expression and mtDNA 6mA level, regulate the oxidative stress and expression of mtDNA coded genes. This study investigated a new molecular mechanism of pancreatic tumorigenesis, and revealed the therapeutic efficacy of XCHT in pancreatic tumorigenesis for the first time.
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Affiliation(s)
- Jun Cai
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, 79 Duolun Road, Tianjin, China
| | - Wenyuan Shen
- Department of Spine Surgery, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, China
| | - Guixian Zhang
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, 79 Duolun Road, Tianjin, China
| | - Xia Li
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, 79 Duolun Road, Tianjin, China
| | - Hongsheng Shen
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, 79 Duolun Road, Tianjin, China
| | - Wenchang Li
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, 79 Duolun Road, Tianjin, China
| | - Cheng Tan
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, 79 Duolun Road, Tianjin, China
| | - Ting Zhang
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, 79 Duolun Road, Tianjin, China
| | - Mengrou Shi
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, 79 Duolun Road, Tianjin, China
| | - Zibo Yang
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, 79 Duolun Road, Tianjin, China
| | - Yuan Li
- Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
| | - Hongbin Liu
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, 79 Duolun Road, Tianjin, China; Health Commission of Heping District, Tianjin, China.
| | - Xiumei Zhao
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, 79 Duolun Road, Tianjin, China.
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14
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Chamarthy S, Mekala JR. Functional importance of glucose transporters and chromatin epigenetic factors in Glioblastoma Multiforme (GBM): possible therapeutics. Metab Brain Dis 2023; 38:1441-1469. [PMID: 37093461 DOI: 10.1007/s11011-023-01207-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 03/22/2023] [Indexed: 04/25/2023]
Abstract
Glioblastoma Multiforme (GBM) is an aggressive brain cancer affecting glial cells and is chemo- and radio-resistant. Glucose is considered the most vital energy source for cancer cell proliferation. During metabolism, hexose molecules will be transported into the cells via transmembrane proteins known as glucose transporter (GLUT). Among them, GLUT-1 and GLUT-3 play pivotal roles in glucose transport in GBM. Knockdown studies have established the role of GLUT-1, and GLUT-3 mediated glucose transport in GBM cells, providing insight into GLUT-mediated cancer signaling and cancer aggressiveness. This review focussed on the vital role of GLUT-1 and GLUT-3 proteins, which regulate glucose transport. Recent studies have identified the role of GLUT inhibitors in effective cancer prevention. Several of them are in clinical trials. Understanding and functional approaches towards glucose-mediated cell metabolism and chromatin epigenetics will provide valuable insights into the mechanism of cancer aggressiveness, cancer stemness, and chemo-resistance in Glioblastoma Multiforme (GBM). This review summarizes the role of GLUT inhibitors, micro-RNAs, and long non-coding RNAs that aid in inhibiting glucose uptake by the GBM cells and other cancer cells leading to the identification of potential therapeutic, prognostic as well as diagnostic markers. Furthermore, the involvement of epigenetic factors, such as microRNAs, in regulating glycolytic genes was demonstrated.
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Affiliation(s)
- Sahiti Chamarthy
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (KLEF), Green Fields, Vaddeswaram, Guntur, Andhra Pradesh, 522302, India
| | - Janaki Ramaiah Mekala
- Department of Biotechnology, Koneru Lakshmaiah Education Foundation (KLEF), Green Fields, Vaddeswaram, Guntur, Andhra Pradesh, 522302, India.
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15
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Zhang N, Tian X, Yan T, Wang H, Zhang D, Lin C, Liu Q, Jiang S. Insights into the role of nucleotide methylation in metabolic-associated fatty liver disease. Front Immunol 2023; 14:1148722. [PMID: 37020540 PMCID: PMC10067741 DOI: 10.3389/fimmu.2023.1148722] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 02/22/2023] [Indexed: 04/07/2023] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disease characterized by fatty infiltration of the liver. In recent years, the MAFLD incidence rate has risen and emerged as a serious public health concern. MAFLD typically progresses from the initial hepatocyte steatosis to steatohepatitis and then gradually advances to liver fibrosis, which may ultimately lead to cirrhosis and carcinogenesis. However, the potential evolutionary mechanisms still need to be clarified. Recent studies have shown that nucleotide methylation, which was directly associated with MAFLD's inflammatory grading, lipid synthesis, and oxidative stress, plays a crucial role in the occurrence and progression of MAFLD. In this review, we highlight the regulatory function and associated mechanisms of nucleotide methylation modification in the progress of MAFLD, with a particular emphasis on its regulatory role in the inflammation of MAFLD, including the regulation of inflammation-related immune and metabolic microenvironment. Additionally, we summarize the potential value of nucleotide methylation in the diagnosis and treatment of MAFLD, intending to provide references for the future investigation of MAFLD.
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Affiliation(s)
- Ni Zhang
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xinchen Tian
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tinghao Yan
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Haochen Wang
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining Medical University, Jining, China
| | - Dengtian Zhang
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining Medical University, Jining, China
| | - Cong Lin
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining Medical University, Jining, China
| | - Qingbin Liu
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining Medical University, Jining, China
- *Correspondence: Qingbin Liu, ; Shulong Jiang,
| | - Shulong Jiang
- Cheeloo College of Medicine, Shandong University, Jinan, China
- Clinical Medical Laboratory Center, Jining First People’s Hospital, Jining Medical University, Jining, China
- *Correspondence: Qingbin Liu, ; Shulong Jiang,
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16
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Warburg effect in colorectal cancer: the emerging roles in tumor microenvironment and therapeutic implications. J Hematol Oncol 2022; 15:160. [PMID: 36319992 PMCID: PMC9628128 DOI: 10.1186/s13045-022-01358-5] [Citation(s) in RCA: 135] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 09/26/2022] [Indexed: 11/07/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. Countless CRC patients undergo disease progression. As a hallmark of cancer, Warburg effect promotes cancer metastasis and remodels the tumor microenvironment, including promoting angiogenesis, immune suppression, cancer-associated fibroblasts formation and drug resistance. Targeting Warburg metabolism would be a promising method for the treatment of CRC. In this review, we summarize information about the roles of Warburg effect in tumor microenvironment to elucidate the mechanisms governing Warburg effect in CRC and to identify novel targets for therapy.
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17
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Liu Y, Chen C, Wang X, Sun Y, Zhang J, Chen J, Shi Y. An Epigenetic Role of Mitochondria in Cancer. Cells 2022; 11:cells11162518. [PMID: 36010594 PMCID: PMC9406960 DOI: 10.3390/cells11162518] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/03/2022] [Accepted: 08/09/2022] [Indexed: 12/14/2022] Open
Abstract
Mitochondria are not only the main energy supplier but are also the cell metabolic center regulating multiple key metaborates that play pivotal roles in epigenetics regulation. These metabolites include acetyl-CoA, α-ketoglutarate (α-KG), S-adenosyl methionine (SAM), NAD+, and O-linked beta-N-acetylglucosamine (O-GlcNAc), which are the main substrates for DNA methylation and histone post-translation modifications, essential for gene transcriptional regulation and cell fate determination. Tumorigenesis is attributed to many factors, including gene mutations and tumor microenvironment. Mitochondria and epigenetics play essential roles in tumor initiation, evolution, metastasis, and recurrence. Targeting mitochondrial metabolism and epigenetics are promising therapeutic strategies for tumor treatment. In this review, we summarize the roles of mitochondria in key metabolites required for epigenetics modification and in cell fate regulation and discuss the current strategy in cancer therapies via targeting epigenetic modifiers and related enzymes in metabolic regulation. This review is an important contribution to the understanding of the current metabolic-epigenetic-tumorigenesis concept.
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Affiliation(s)
- Yu’e Liu
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
| | - Chao Chen
- Department of Neurosurgery, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China
| | - Xinye Wang
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
| | - Yihong Sun
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
| | - Jin Zhang
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Juxiang Chen
- Department of Neurosurgery, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China
- Correspondence: (J.C.); (Y.S.)
| | - Yufeng Shi
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
- Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai 200092, China
- Correspondence: (J.C.); (Y.S.)
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18
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Markouli M, Strepkos D, Papavassiliou KA, Papavassiliou AG, Piperi C. Crosstalk of Epigenetic and Metabolic Signaling Underpinning Glioblastoma Pathogenesis. Cancers (Basel) 2022; 14:2655. [PMID: 35681635 PMCID: PMC9179868 DOI: 10.3390/cancers14112655] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/14/2022] [Accepted: 05/24/2022] [Indexed: 02/06/2023] Open
Abstract
Metabolic alterations in neoplastic cells have recently gained increasing attention as a main topic of research, playing a crucial regulatory role in the development and progression of tumors. The interplay between epigenetic modifications and metabolic pathways in glioblastoma cells has emerged as a key pathogenic area with great potential for targeted therapy. Epigenetic mechanisms have been demonstrated to affect main metabolic pathways, such as glycolysis, pentose phosphate pathway, gluconeogenesis, oxidative phosphorylation, TCA cycle, lipid, and glutamine metabolism by modifying key regulatory genes. Although epigenetic modifications can primarily promote the activity of metabolic pathways, they may also exert an inhibitory role. In this way, they participate in a complex network of interactions that regulate the metabolic behavior of malignant cells, increasing their heterogeneity and plasticity. Herein, we discuss the main epigenetic mechanisms that regulate the metabolic pathways in glioblastoma cells and highlight their targeting potential against tumor progression.
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19
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Wang X, Wang Z, Huang R, Lu Z, Chen X, Huang D. UPP1 Promotes Lung Adenocarcinoma Progression through Epigenetic Regulation of Glycolysis. Aging Dis 2022; 13:1488-1503. [PMID: 36186123 PMCID: PMC9466982 DOI: 10.14336/ad.2022.0218] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/18/2022] [Indexed: 11/01/2022] Open
Affiliation(s)
- Xuan Wang
- Department of Thoracic Surgery Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China.
- Correspondence should be addressed to: Dr. Dayu Huang (), Dr. Xiaofeng Chen (); Dr. Xuan Wang ().Department of Thoracic Surgery Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Zheng Wang
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Renhong Huang
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhouyi Lu
- Department of Thoracic Surgery Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China.
| | - Xiaofeng Chen
- Department of Thoracic Surgery Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China.
- Correspondence should be addressed to: Dr. Dayu Huang (), Dr. Xiaofeng Chen (); Dr. Xuan Wang ().Department of Thoracic Surgery Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
| | - Dayu Huang
- Department of Thoracic Surgery Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China.
- Correspondence should be addressed to: Dr. Dayu Huang (), Dr. Xiaofeng Chen (); Dr. Xuan Wang ().Department of Thoracic Surgery Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
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20
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Kamal S, Derbala HA, Alterary SS, Ben Bacha A, Alonazi M, El-Ashrey MK, Eid El-Sayed NN. Synthesis, Biological, and Molecular Docking Studies on 4,5,6,7-Tetrahydrobenzo[ b]thiophene Derivatives and Their Nanoparticles Targeting Colorectal Cancer. ACS OMEGA 2021; 6:28992-29008. [PMID: 34746589 PMCID: PMC8567357 DOI: 10.1021/acsomega.1c04063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 09/29/2021] [Indexed: 06/13/2023]
Abstract
Initiation of colorectal carcinogenesis may be induced by chromosomal instability caused by oxidative stress or indirectly by bacterial infections. Moreover, proliferating tumor cells are characterized by reprogrammed glucose metabolism, which is associated with upregulation of PDK1 and LDHA enzymes. In the present study, some 4,5,6,7-tetrahydrobenzo[b]thiophene derivatives in addition to Fe3O4 and Fe3O4/SiO2 nanoparticles (NPs) supported with a new Schiff base were synthesized for biological evaluation as PDK1 and LDHA inhibitors as well as antibacterial, antioxidant, and cytotoxic agents on LoVo and HCT-116 cells of colorectal cancer (CRC). The results showed that compound 1b is the most active as PDK1 and LDHA inhibitor with IC50 values (μg/mL) of 57.10 and 64.10 compared to 25.75 and 15.60, which were produced by the standard inhibitors sodium dichloroacetate and sodium oxamate, respectively. NPs12a,b and compound 1b exhibited the strongest antioxidant properties with IC50 values (μg/mL) of 80.0, 95.0, and 110.0 μg/mL, respectively, compared to 54.0 μg/mL, which was produced by butylated hydroxy toluene. Moreover, NPs12a and carbamate derivative 3b exhibited significant cytotoxic activities with IC50 values (μg/mL) of 57.15 and 81.50 (LoVo cells) and 60.35 and 71.00 (HCT-116 cells). Thus, NPs12a and compound 3b would be considered as promising candidates suitable for further optimization to develop new chemopreventive and chemotherapeutic agents against these types of CRC cell lines. Besides, molecular docking in the colchicine binding site of the tubulin (TUB) domain revealed a good binding affinity of 3b to the protein; in addition, the absorption, distribution, metabolism, and excretion (ADME) analyses showed its desirable drug-likeness and oral bioavailability characteristics.
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Affiliation(s)
- Shimaa Kamal
- Chemistry
Department, Faculty of Science, Ain Shams
University, Abbassia, Cairo 11566, Egypt
| | - Hamed Ahmed Derbala
- Chemistry
Department, Faculty of Science, Ain Shams
University, Abbassia, Cairo 11566, Egypt
| | - Seham Soliman Alterary
- Department
of Chemistry, College of Science, King Saud
University, P.O. Box 50013, Riyadh 11523, Saudi Arabia
| | - Abir Ben Bacha
- Biochemistry
Department, College of Science, King Saud
University, P.O. Box 22452, Riyadh 11495, Saudi Arabia
| | - Mona Alonazi
- Biochemistry
Department, College of Science, King Saud
University, P.O. Box 22452, Riyadh 11495, Saudi Arabia
| | - Mohamed Kandeel El-Ashrey
- Pharmaceutical
Chemistry Department, Molecular Modeling Unit, Faculty of Pharmacy, Cairo University, Kasr Elini Street, Cairo 11562, Egypt
| | - Nahed Nasser Eid El-Sayed
- National
Organization for Drug Control and Research, Egyptian Drug Authority, 51 Wezaret El-Zerra Street, Giza 35521, Egypt
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21
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Patra S, Elahi N, Armorer A, Arunachalam S, Omala J, Hamid I, Ashton AW, Joyce D, Jiao X, Pestell RG. Mechanisms Governing Metabolic Heterogeneity in Breast Cancer and Other Tumors. Front Oncol 2021; 11:700629. [PMID: 34631530 PMCID: PMC8495201 DOI: 10.3389/fonc.2021.700629] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 08/30/2021] [Indexed: 12/14/2022] Open
Abstract
Reprogramming of metabolic priorities promotes tumor progression. Our understanding of the Warburg effect, based on studies of cultured cancer cells, has evolved to a more complex understanding of tumor metabolism within an ecosystem that provides and catabolizes diverse nutrients provided by the local tumor microenvironment. Recent studies have illustrated that heterogeneous metabolic changes occur at the level of tumor type, tumor subtype, within the tumor itself, and within the tumor microenvironment. Thus, altered metabolism occurs in cancer cells and in the tumor microenvironment (fibroblasts, immune cells and fat cells). Herein we describe how these growth advantages are obtained through either “convergent” genetic changes, in which common metabolic properties are induced as a final common pathway induced by diverse oncogene factors, or “divergent” genetic changes, in which distinct factors lead to subtype-selective phenotypes and thereby tumor heterogeneity. Metabolic heterogeneity allows subtyping of cancers and further metabolic heterogeneity occurs within the same tumor mass thought of as “microenvironmental metabolic nesting”. Furthermore, recent findings show that mutations of metabolic genes arise in the majority of tumors providing an opportunity for the development of more robust metabolic models of an individual patient’s tumor. The focus of this review is on the mechanisms governing this metabolic heterogeneity in breast cancer.
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Affiliation(s)
- Sayani Patra
- Pensylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, United States.,Xavier University School of Medicine at Aruba, Oranjestad, Aruba
| | - Naveed Elahi
- Pensylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, United States.,Xavier University School of Medicine at Aruba, Oranjestad, Aruba
| | - Aaron Armorer
- Pensylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, United States.,Xavier University School of Medicine at Aruba, Oranjestad, Aruba
| | - Swathi Arunachalam
- Pensylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, United States.,Xavier University School of Medicine at Aruba, Oranjestad, Aruba
| | - Joshua Omala
- Pensylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, United States.,Xavier University School of Medicine at Aruba, Oranjestad, Aruba
| | - Iman Hamid
- Pensylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, United States.,Xavier University School of Medicine at Aruba, Oranjestad, Aruba
| | - Anthony W Ashton
- Xavier University School of Medicine at Aruba, Oranjestad, Aruba.,Program in Cardiovascular Medicine, Lankenau Institute for Medical Research, Wynnewood, PA, United States
| | - David Joyce
- Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Crawley, WA, Australia
| | - Xuanmao Jiao
- Pensylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, United States.,Xavier University School of Medicine at Aruba, Oranjestad, Aruba
| | - Richard G Pestell
- Pensylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, United States.,Xavier University School of Medicine at Aruba, Oranjestad, Aruba.,Cancer Center, Wistar Institute, Philadelphia, PA, United States
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Yu Z, Hou Y, Zhou W, Zhao Z, Liu Z, Fu A. The effect of mitochondrial transplantation therapy from different gender on inhibiting cell proliferation of malignant melanoma. Int J Biol Sci 2021; 17:2021-2033. [PMID: 34131403 PMCID: PMC8193273 DOI: 10.7150/ijbs.59581] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 04/23/2021] [Indexed: 01/16/2023] Open
Abstract
Today mitochondria are considered much more than a energy plant in cells. Mitochondrial transplantation therapy has been an active research area for treating mitochondria-associated diseases from animal studies to clinical trials. However, the specific mechanism involved in the anti-tumor activity of healthy mitochondria remain to be characterized. Here we investigate the signal mechanism and gender difference of mitochondrial transplantation therapy against malignant melanoma. In the study, we administrated intact mitochondria extracted from mouse livers respectively to the mice bearing malignantly subcutaneous and metastatic melanoma, and identified the signal mechanism responsible for the mitochondrial treatment through transcriptomic analysis. Meanwhile, the efficiency of female mitochondria and male mitochondria was compared in the cultured melanoma cells and transplanted melanoma in mice. The results suggested that the mitochondria significantly inhibited the tumor cell proliferation in vitro through cell cycle arrest and induction of cell apoptosis. In the melanoma-bearing mice, the mitochondria retard the tumor growth and lung migration, and the transcriptomic analysis indicated that general chromosome silencing was strongly associated with the mitochondria against melanoma after the mitochondrial transplantation on the metastasis melanoma. Moreover, the anti-tumor activity of mitochondria from female animals was more efficient in comparison to the males, and the female mitochondria could probably induce more persuasive mitochondria-nuclear communication than the mitochondria from male mice. The study identifies the anti-tumor mechanism of the mitochondrial transplantation therapy, and provides a novel insight into the effect of mitochondria from different gender.
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Affiliation(s)
| | | | | | | | | | - Ailing Fu
- School of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
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Baryla I, Pluciennik E, Kośla K, Wojcik M, Zieleniak A, Zurawska-Klis M, Cypryk K, Wozniak LA, Bednarek AK. Identification of a novel association for the WWOX/HIF1A axis with gestational diabetes mellitus (GDM). PeerJ 2021; 9:e10604. [PMID: 33520443 PMCID: PMC7811782 DOI: 10.7717/peerj.10604] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 11/28/2020] [Indexed: 12/12/2022] Open
Abstract
Background Although the WW-domain-containing oxidoreductase (WWOX)/Hypoxia-inducible factor 1 (HIF1) pathway is a well-known regulator of cellular glucose and energy metabolism in pathophysiological processes, its role in gestational diabetes mellitus (GDM), remains elusive. We undertook this study to determine the effect of WWOX/HIF1A signaling on the expression of glucose metabolism genes in GDM patients. Methods Leukocytes were obtained from 135 pregnant women with (n = 98) or without (n = 37) GDM and, in turn, 3 months (n = 8) and 1 year (n = 12) postpartum. Quantitative RT-PCR was performed to determine gene expression profiles of the WWOX/HIF1A-related genes, including those involved in glucose transport (SLC2A1, SLC2A4), glycolytic pathway (HK2, PKM2, PFK, LDHA), Wnt pathway (DVL2, CTNNB1), and inflammatory response (NFKB1). Results GDM patients displayed a significant downregulation of WWOX with simultaneous upregulation of HIF1A which resulted in approximately six times reduction in WWOX/HIF1A ratio. As a consequence, HIF1A induced genes (SLC2A1, HK2, PFK, PKM) were found to be overexpressed in GDM compared to normal pregnancy and negative correlate with WWOX/HIF1A ratio. The postpartum WWOX expression was higher than during GDM, but its level was comparable to that observed in normal pregnancy. Conclusions The obtained results suggest a significant contribution of the WWOX gene to glucose metabolism in patients with gestational diabetes. Decreased WWOX expression in GDM compared to normal pregnancy, and in particular reduction of WWOX/HIF1A ratio, indicate that WWOX modulates HIF1α activity in normal tissues as described in the tumor. The effect of HIF1α excessive activation is to increase the expression of genes encoding proteins directly involved in the glycolysis which may lead to pathological changes in glucose metabolism observed in gestational diabetes.
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Affiliation(s)
- Izabela Baryla
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
| | - Elzbieta Pluciennik
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
| | - Katarzyna Kośla
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
| | - Marzena Wojcik
- Department of Structural Biology, Medical University of Lodz, Lodz, Poland
| | - Andrzej Zieleniak
- Department of Structural Biology, Medical University of Lodz, Lodz, Poland
| | - Monika Zurawska-Klis
- Department of Internal Diseases and Diabetology, Medical University of Lodz, Lodz, Poland
| | - Katarzyna Cypryk
- Department of Internal Diseases and Diabetology, Medical University of Lodz, Lodz, Poland
| | | | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
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