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Kar E, Övenler Z, Hacıoğlu C, Kar F. Boric Acid Induces Oxidative Damage and Apoptosis Through SEMA3A/PLXNA1/NRP1 Signalling Pathway in U251 Glioblastoma Cell. J Cell Mol Med 2025; 29:e70578. [PMID: 40318008 PMCID: PMC12049150 DOI: 10.1111/jcmm.70578] [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: 01/07/2025] [Revised: 04/17/2025] [Accepted: 04/21/2025] [Indexed: 05/07/2025] Open
Abstract
Glioblastoma is one of the deadliest cancers with a very low chance of survival. Glioblastomas have a poor prognosis because of their infiltrative nature, which makes them difficult to totally isolate with rigorous surgery, radiation, and chemotherapy. Our aim in this study was to investigate the efficacy of boric acid, which has anti-cancer properties, on glioblastoma, which has very limited treatment options. U251 human glioblastoma cell lines were treated with IC25 (15.62 μg/mL), IC50 (31.25 μg/mL) and IC75 (62.5 μg/mL) doses of boric acid. Cell viability and proliferation levels were tested. At the same time, the activity of boric acid on cells was tested through oxidative stress, apoptosis, and semaphorin signalling pathway parameters. Our findings indicate that boric acid induced dose-dependent oxidative stress, cellular growth inhibition, apoptosis and morphological changes in U251 cells. Additionally, treatments with increasing amounts of boric acid resulted in a rise in the production of biomarkers of the semaphorin pathway, which may limit cell growth and proliferation. We found that boric acid activates apoptosis by triggering ROS formation at high doses and at the same time inhibits cell proliferation by increasing semaphorin signalling pathway expressions. Boric acid may act as an anti-cancer agent by activating different mechanisms in a dose-dependent manner.
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Affiliation(s)
- Ezgi Kar
- Department of Nutrition and Dietetics, Faculty of Health SciencesKutahya Health Sciences UniversityKutahyaTurkey
| | - Zeynep Övenler
- Faculty of MedicineKutahya Health Sciences UniversityKutahyaTurkey
| | - Ceyhan Hacıoğlu
- Department of Medical Biochemistry, Faculty of MedicineDuzce UniversityDuzceTurkey
| | - Fatih Kar
- Department of Medical Biochemistry, Faculty of MedicineKutahya Health Sciences UniversityKutahyaTurkey
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Peng L, You J, Liu R, Long Y, Song G, Benjakul S, Xiong S, Rahman Z, Huang Q, Chen S, Yin T. Fasting influences the muscle quality of fish during transportation by regulating the balance between energy metabolism and ammonia nitrogen stress. J Adv Res 2025:S2090-1232(25)00207-3. [PMID: 40154734 DOI: 10.1016/j.jare.2025.03.047] [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: 12/25/2024] [Revised: 03/24/2025] [Accepted: 03/24/2025] [Indexed: 04/01/2025] Open
Abstract
INTRODUCTION Fasting has been widely applied in aquaculture to improve the welfare of fish. However, fasting regulate the interplay of energy metabolism and ammonia nitrogen stress on the muscle quality unclear. OBJECTIVES To clarify the impact of fasting on the energy metabolism, ammonia nitrogen stress, and muscle quality. METHODS Blunt snout bream (Megalobrama amblycephala) were fasted for different days before transportation. Then changes in energy metabolism, stress response, cell apoptosis, and muscle quality were assessed using UPLC-QTOF-MS untargeted metabolomics along with classical molecular biology techniques. RESULTS Our findings revealed that short-term fasting (2-3 d) effectively alleviated ammonia nitrogen stress. The cortisol and superoxide dismutase decreased gradually as the fasting time was extended from 0 to 3 d, with decreased of 28.60 % and 55.39 %. Regarding the energy reserves, a reduction in muscle glycogen, protein, and lipid content was observed after fasting. These changes were attributed to the intensified tricarboxylic acid cycle, amino acid metabolism, and lipid metabolism. Furthermore, fasting enhanced the glycolysis of glycogen, and the gluconeogenesis of glutamic acid and aspartic acid to generate adenosine triphosphate. Notably, short-term fasting alleviated muscle cell apoptosis via down-regulating expression of Caspase 9 and Bax. Moreover, the water holding capacity, shear force, and springiness were better improved after fasting 2 d, reaching 79.88 %, 407.11 g, and 0.78 g, respectively. However, when fasting was extended to 4 d, there was a decrease in energy substances in the fish muscle and an increase in oxidative stress and apoptosis, thereby inducing a decrease in the muscle quality. CONCLUSION Our data concluded that fasting affects cell apoptosis by regulating the balance between energy metabolism and stress, ultimately impacting muscle quality. For long-distance transportation, a fasting period of 2-3 d is optimal.
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Affiliation(s)
- Ling Peng
- College of Food Science and Technology/National R&D Branch Center for Conventional Freshwater Fish Processing (Wuhan), Huazhong Agricultural University, Wuhan 430070, China
| | - Juan You
- College of Food Science and Technology/National R&D Branch Center for Conventional Freshwater Fish Processing (Wuhan), Huazhong Agricultural University, Wuhan 430070, China
| | - Ru Liu
- College of Food Science and Technology/National R&D Branch Center for Conventional Freshwater Fish Processing (Wuhan), Huazhong Agricultural University, Wuhan 430070, China
| | - Yong Long
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Guili Song
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Soottawat Benjakul
- Department of Food Technology, Faculty of Agro-industry, Prince of Songkla University, 15 Kanchanawanich Road, Hat Yai 90112, Thailand
| | - Shanbai Xiong
- College of Food Science and Technology/National R&D Branch Center for Conventional Freshwater Fish Processing (Wuhan), Huazhong Agricultural University, Wuhan 430070, China
| | - Ziaur Rahman
- College of Food Science and Technology/National R&D Branch Center for Conventional Freshwater Fish Processing (Wuhan), Huazhong Agricultural University, Wuhan 430070, China
| | - Qiling Huang
- College of Food Science and Technology/National R&D Branch Center for Conventional Freshwater Fish Processing (Wuhan), Huazhong Agricultural University, Wuhan 430070, China
| | - Sheng Chen
- Institute of Agricultural Products Processing and Nuclear-Agricultural Technology, Hubei Academy of Agricultural Sciences, Wuhan 430064, China
| | - Tao Yin
- College of Food Science and Technology/National R&D Branch Center for Conventional Freshwater Fish Processing (Wuhan), Huazhong Agricultural University, Wuhan 430070, China.
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Wurlina W, Meles DK, Mustofa I, Khairullah AR, Putra DMS, Suwasanti N, Akintunde AO, Utama S, Mulyati S, Wasito W, Raissa R, Ahmad RZ, Julaeha J, Ekawasti F. Alkaloid fraction of Achyranthes aspera Linn triggers breast cancer apoptosis in mice ( Mus musculus) model. Open Vet J 2025; 15:1279-1288. [PMID: 40276193 PMCID: PMC12017709 DOI: 10.5455/ovj.2025.v15.i3.19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Accepted: 02/15/2025] [Indexed: 04/26/2025] Open
Abstract
Background Breast cancer affects women of various ages, and its recurrence is a significant cause of death. The search for potent anticancer compounds of herbal origin with well-defined mechanisms of action is an essential focus of current research. Aim This study aimed to investigate the effects of alkaloids in Achyranthes aspera Linn (AAL) leaf extract on necrosis, apoptosis, and related molecular markers, namely, cyclin-dependent kinase 1, Bcl-2 associated X-protein (Bax), rat sarcoma virus (Ras), cytochrome (Cyt) c, and apoptotic activating factor-1 (Apaf-1), in mice models. Methods Thirty mice with breast cancer were randomly divided into five groups. The negative control group only received distilled water daily. Mice in the positive control group (PCG) were administered methotrexate (15 mg/Kg) daily. The T1, T2, and T3 groups received oral orally at 75, 100, and 125 mg/Kg body weight daily for 30 days, respectively. On day 31, all mice were euthanized for the preparation of histological specimens of the mammary glands. The negative control group had the lowest number of apoptotic cells, Apaf-1, Cyt C, and Bax expression, and the highest number of viable cancer cells and Ras expression. Results The percentages of necrotic cells and breast cancer-expressed CDK-1 were not significantly (p > 0.05) different among groups. The percentage of apoptotic cells, Apaf-1, and Cyt c, was highest in T3. Conversely, the percentage of viable cells and breast cancer-expressing Ras was lowest in T3. Conclusion Treatment with 125 mg/Kg AAL suppressed cancer cell growth in breast cancer-bearing mice. Further research is necessary to determine the complete signaling mechanism.
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Affiliation(s)
- Wurlina Wurlina
- Division of Veterinary Reproduction, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Dewa Ketut Meles
- Division of Basic Veterinary Medicine, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Imam Mustofa
- Division of Veterinary Reproduction, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Aswin Rafif Khairullah
- Research Center for Veterinary Science, National Research and Innovation Agency (BRIN), Bogor, Indonesia
| | | | - Niluh Suwasanti
- Department of Clinical Pathology, Faculty of Medicine, Universitas Katolik Widya Mandala Surabaya, Surabaya, Indonesia
| | - Adeyinka Oye Akintunde
- Department of Agriculture and Industrial Technology, Babcock University, Ilishan Remo State, Nigeria
| | - Suzanita Utama
- Division of Veterinary Reproduction, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Sri Mulyati
- Division of Veterinary Reproduction, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Wasito Wasito
- Research Center for Veterinary Science, National Research and Innovation Agency (BRIN), Bogor, Indonesia
| | - Ricadonna Raissa
- Department of Pharmacology, Faculty of Veterinary Medicine, Universitas Brawijaya, Malang, Indonesia
| | - Riza Zainuddin Ahmad
- Research Center for Veterinary Science, National Research and Innovation Agency (BRIN), Bogor, Indonesia
| | - Julaeha Julaeha
- Research Center for Preclinical and Clinical Medicine, National Research and Innovation Agency (BRIN), Bogor, Indonesia
| | - Fitrine Ekawasti
- Research Center for Veterinary Science, National Research and Innovation Agency (BRIN), Bogor, Indonesia
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Meng Y, Si Y, Guo T, Zhao W, Zhang L, Wang Y, Wang L, Sun K, Feng S. Ethoxychelerythrine as a potential therapeutic strategy targets PI3K/AKT/mTOR induced mitochondrial apoptosis in the treatment of colorectal cancer. Sci Rep 2025; 15:6642. [PMID: 39994297 PMCID: PMC11850888 DOI: 10.1038/s41598-025-91251-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 02/19/2025] [Indexed: 02/26/2025] Open
Abstract
Several alkaloids found in the Zanthoxylum genus have demonstrated significant anticancer activity. However, the antitumor effects of Ethoxychelerythrine (Eth) have not been previously reported. Cell viability, colony formation, apoptosis and cell cycle analysis, intracellular and reactive oxygen species (ROS), mitochondrial membrane potential (MMP) levels of Eth against SW480 cells were evaluated. Subcutaneously transplanted SW480 cells model was used to determine the effect of Eth on tumor growth in vivo. Inflammation levels, angiogenic factors, pathological observations, quantitative reverse-transcription PCR (qRT-PCR), quantitative proteomics, metabolite profiles and western blotting were conducted. It found that Eth significantly inhibited the proliferation of SW480 and HT29 cells in vitro, with stronger inhibitory activity observed against SW480 cells. Therefore, subsequent studies focused on SW480 cells. In vitro, we observed that Eth arrested the cell cycle at the G0/G1 phase, decreased MMP levels, elevated cellular ROS levels, and induced mitochondrial apoptosis. In vitro, Eth significantly inhibited tumor proliferation and metastasis, and regulated the molecule levels of angiogenesis and inflammatory factors in serum, as well as apoptotic protein in tumor tissues. The serum proteomic revealed that the differential proteins were primarily involved in the PI3K/AKT/mTOR pathway, including laminin β1 (Lamb1), and type I collagen (Col1a1). Metabolomics showed that many abnormal levels of metabolites regulated by the PI3K/AKT/mTOR pathway were obviously reversed towards normal levels after Eth intervention. The correlation analysis between the two-omics revealed that different proteins in the PI3K/AKT pathway, particularly lactate dehydrogenase B (LDHB) and glutathione synthetase (GSS), can interact with most of different metabolites. In summary, Eth exerts anti-tumour effects by inhibiting the activation of the PI3K/AKT/mTOR pathway, which in turn activates mitochondrial apoptosis. Eth may be considered in the development of drugs for relieving colon cancer patients in the future.
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Affiliation(s)
- Yaqin Meng
- Department of Pharmacy, Henan University of Chinese Medicine, NO 156 JinshuiEast Road, Zhengzhou, 450046, China
- School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou, 730050, China
| | - Yanpo Si
- Department of Pharmacy, Henan University of Chinese Medicine, NO 156 JinshuiEast Road, Zhengzhou, 450046, China
| | - Tao Guo
- Department of Pharmacy, Henan University of Chinese Medicine, NO 156 JinshuiEast Road, Zhengzhou, 450046, China.
| | - Weiwei Zhao
- Department of Integrated Therapy, Fudan University Shanghai Cancer Center, No 270 Dong'An Road, Shanghai, 200032, China.
| | - Liping Zhang
- Department of Pharmacy, Henan University of Chinese Medicine, NO 156 JinshuiEast Road, Zhengzhou, 450046, China
| | - Ya Wang
- School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou, 730050, China
| | - Lianping Wang
- Lanzhou Foci Pharmaceutical Co., Ltd, Lanzhou, 730050, China
| | - Ke Sun
- Lanzhou Foci Pharmaceutical Co., Ltd, Lanzhou, 730050, China
| | - Shuying Feng
- Medical College, Henan University of Chinese Medicine, NO 156 JinshuiEast Road, Zhengzhou, 450046, China.
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Li C, Zhao Y, He C, Wang X, Ren Q, Gai X, Wang H. IL-17E facilitates cell proliferation and epithelial-mesenchymal transition in A549 NSCLC cells by regulating the NF-κB pathway. Pathol Res Pract 2025; 266:155792. [PMID: 39753017 DOI: 10.1016/j.prp.2024.155792] [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: 08/22/2024] [Accepted: 12/23/2024] [Indexed: 05/01/2025]
Abstract
OBJECTIVE Interleukin-17 E (IL-17E) is a pro-inflammatory cytokine that participates in the inflammatory response and tumorigenesis. However, the function of IL-17E in non-small cell lung cancer (NSCLC) remains largely unknown. METHODS The clinical value of IL-17E was determined by immunohistochemistry (IHC) in 75 cases of NSCLC tissues. Furthermore, A549 cells were added with recombinant human IL-17E (rhIL-17E) or transfected with IL-17E siRNAs to evaluate the impact on cell proliferation, apoptosis, and epithelial-mesenchymal transition (EMT), as well as explore the link between IL-17E and the NF-κB pathway. Experimental techniques include CCK-8, EdU, colony formation, RT-qPCR, western blotting, flow cytometry, wound-healing, transwell and immunofluorescence assay. RESULTS IL-17E levels was elevated in NSCLC tissues and cells, which was related to higher TNM staging, positive lymph node metastasis and decreased tumor differentiation degree. Exogenous recombinant human IL-17E (rhIL-17E) treatment promoted cell proliferation, reduced cell apoptosis, and increased the level of Bcl-2/BAX. Moreover, it enhanced cell migration, invasion, EMT and phosphorylation levels of NF-κB p65. Inversely, knocking down endogenous IL-17E in A549 cells had the opposite effect. Blocking the NF-κB pathway with BAY-117082 reduced IL-17E expression and reversed the malignant effects induced by IL-17E on A549 cells. CONCLUSION IL-17E facilitates NSCLC progression by promoting cell proliferation and EMT via the NF-κB pathway. IL-17E could serve as a potential strategy for NSCLC treatment.
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Affiliation(s)
- Chun Li
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin 132013, China
| | - Ying Zhao
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin 132013, China
| | - Chengyuan He
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin 132013, China
| | - Xingxiang Wang
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin 132013, China
| | - Qiaotong Ren
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin 132013, China
| | - Xiaodong Gai
- Department of Immunology, School of Basic Medical Sciences, Beihua University, Jilin 132013, China.
| | - Hefei Wang
- Department of Obstetrics and Gynaecology, The First Hospital of Jilin University, Changchun 130021, China.
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Nethi SK, Kothadiya S, White BM, Rachagani S, Bardhan R, Mallapragada SK. Polyanhydride Copolymer-Based Niclosamide Nanoparticles for Inhibiting Triple-Negative Breast Cancer: Metabolic Responses and Synergism with Paclitaxel. ACS APPLIED MATERIALS & INTERFACES 2024; 16:70362-70377. [PMID: 39666980 DOI: 10.1021/acsami.4c17961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2024]
Abstract
The heterogeneity of tumors and the lack of effective therapies have resulted in triple-negative breast cancer (TNBC) exhibiting the least favorable outcomes among breast cancer subtypes. TNBC is characterized by its aggressive nature, often leading to high rates of relapse, metastasis, and mortality. Niclosamide (Nic), an Food and Drug Administration-approved anthelmintic drug, has been repurposed for cancer treatment; however, its application for TNBC is hindered by significant challenges, including strong hydrophobicity, poor aqueous solubility, and low bioavailability. This study aimed to develop Nic nanoparticles (Nic NPs) using biodegradable and biocompatible polyanhydride copolymers to enhance Nic's bioavailability and therapeutic efficacy. Nic NPs effectively inhibited migration, proliferation, and clonogenicity in both murine and human TNBC cells, inducing apoptosis and suppressing STAT3 signaling. For the first time, we utilized Raman spectroscopy and Seahorse extracellular flux assays to demonstrate the metabolic responses of TNBC cells to Nic NPs, revealing significant metabolic alterations, including the inhibition of mitochondrial respiration and glycolysis. Additionally, this study is the first to explore the combination therapy of repurposed Nic with the approved chemotherapeutic agent paclitaxel in the 4T1 TNBC immunocompetent mouse model. The combination of Nic NPs and paclitaxel significantly reduced tumor growth without adversely affecting the body weight of tumor-bearing mice. In summary, these findings suggest that Nic NPs could serve as a promising component in combination therapies for the effective treatment of TNBC.
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Affiliation(s)
- Susheel Kumar Nethi
- Department of Chemical and Biological Engineering, Iowa State University, Ames, Iowa50011, United States
- Nanovaccine Institute, Iowa State University, Ames, Iowa50011, United States
| | - Siddhant Kothadiya
- Department of Chemical and Biological Engineering, Iowa State University, Ames, Iowa50011, United States
| | - Brianna M White
- Department of Chemical and Biological Engineering, Iowa State University, Ames, Iowa50011, United States
| | - Satyanarayana Rachagani
- Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, Missouri 65211, United States
- Roy Blunt NextGen Precision Health, University of Missouri, Columbia, Missouri 65211, United States
| | - Rizia Bardhan
- Department of Chemical and Biological Engineering, Iowa State University, Ames, Iowa50011, United States
- Nanovaccine Institute, Iowa State University, Ames, Iowa50011, United States
| | - Surya K Mallapragada
- Department of Chemical and Biological Engineering, Iowa State University, Ames, Iowa50011, United States
- Nanovaccine Institute, Iowa State University, Ames, Iowa50011, United States
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Aydemir E, Odabaş Köse E, Özkaya Gül S, Korkut A, Kilit AC, Celep ME, Yavuz M, Göktürk RS, Sarikurkcu C. Phytochemical and Biological Investigations of Crude Extracts of Astragalus pisidicus. Pharmaceuticals (Basel) 2024; 18:10. [PMID: 39861073 PMCID: PMC11768461 DOI: 10.3390/ph18010010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/13/2024] [Accepted: 12/23/2024] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Astragalus L. is a genus of the Fabaceae family, encompassing over 3000 species globally, with 380 species found in Turkey. This is the inaugural examination of the phytochemical, antioxidant, antibacterial, and cytotoxic properties of Astragalus pisidicus. Methods: The water and methanolic fractions of four parts (stems, flowers, leaves, root) as well as the whole plant were quantified and identified by Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometry (LC-ESI-MS/MS) analysis. Cell death was assessed using the WST-1 assay, while apoptosis was identified by colorimetric protease assay for caspase 2, -3, -6, -8, and -9, as well as cellular DNA fragmentation assay. Antioxidant activity of A. pisidicus water and methanolic extracts was investigated with eight different assays. Antimicrobial activities of the extracts were evaluated against 16 bacterial strains by disc diffusion and broth microdilution methods. Results: A total of 13 phytochemicals were detected in the extracts at various concentrations. Hesperidin (147-40,174 µg/g extract) and hyperoside (363-2677 µg/g extract) comprised the principal constituents among the extracts. Fm (IC50 = 9.57 µg/mL), Rm (IC50 = 14.89 µg/mL), and Sm (IC50 = 9.57 µg/mL) were evaluated as active crude extracts on H1299, HT-29, and Panc-1 cells, while Rm (IC50 = 32.057 µg/mL) and Fm (IC50 = 64.25 µg/mL) were assessed as moderately active on MCF-7 and 22RV1 cells, respectively. The elevation of caspase 2, 3, 6, 8, and 9 enzyme activities, along with DNA fragmentation, signifies that the mode of cell death is apoptosis. According to the disc diffusion test results, Fm, Lm, Sm, and WPm extracts exhibited antimicrobial activity against gram (+) bacteria. Conclusions: A. pisidicus elicited apoptotic cell death in cancer cells selectively by the activation of caspases and subsequent DNA fragmentation and may serve as a novel source of an apoptosis-inducing anticancer drug.
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Affiliation(s)
- Esra Aydemir
- Department of Biology, Faculty of Science, Akdeniz University, TR-07058 Antalya, Turkey; (S.Ö.G.); (A.K.); (M.Y.); (R.S.G.)
| | - Elif Odabaş Köse
- Medical Laboratory Program, Vocational School of Health Services, Akdeniz University, TR-07058 Antalya, Turkey;
| | - Serap Özkaya Gül
- Department of Biology, Faculty of Science, Akdeniz University, TR-07058 Antalya, Turkey; (S.Ö.G.); (A.K.); (M.Y.); (R.S.G.)
| | - Alaaddin Korkut
- Department of Biology, Faculty of Science, Akdeniz University, TR-07058 Antalya, Turkey; (S.Ö.G.); (A.K.); (M.Y.); (R.S.G.)
| | - A. Cansu Kilit
- Biomedical Device Technology Program, Department of Electronics and Automation, Technical Sciences Vocational School, Akdeniz University, TR-07058 Antalya, Turkey;
| | - Mehmet Engin Celep
- Department of Pharmacognosy, Faculty of Pharmacy, Yeditepe University, Atasehir, TR-34755 Istanbul, Turkey;
| | - Mustafa Yavuz
- Department of Biology, Faculty of Science, Akdeniz University, TR-07058 Antalya, Turkey; (S.Ö.G.); (A.K.); (M.Y.); (R.S.G.)
| | - R. Süleyman Göktürk
- Department of Biology, Faculty of Science, Akdeniz University, TR-07058 Antalya, Turkey; (S.Ö.G.); (A.K.); (M.Y.); (R.S.G.)
| | - Cengiz Sarikurkcu
- Department of Analytical Chemistry, Faculty of Pharmacy, Afyonkarahisar Health Sciences University, TR-03100 Afyonkarahisar, Turkey;
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Bandyopadhyay D, Tran ET, Patel RA, Luetzen MA, Cho K, Shriver LP, Patti GJ, Varvares MA, Ford DA, McCommis KS, Ray RB. Momordicine-I suppresses head and neck cancer growth by modulating key metabolic pathways. Cell Commun Signal 2024; 22:597. [PMID: 39696286 DOI: 10.1186/s12964-024-01951-w] [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: 08/12/2024] [Accepted: 11/20/2024] [Indexed: 12/20/2024] Open
Abstract
One of the hallmarks of cancer is metabolic reprogramming which controls cellular homeostasis and therapy resistance. Here, we investigated the effect of momordicine-I (M-I), a key bioactive compound from Momordica charantia (bitter melon), on metabolic pathways in human head and neck cancer (HNC) cells and a mouse HNC tumorigenicity model. We found that M-I treatment on HNC cells significantly reduced the expression of key glycolytic molecules, SLC2A1 (GLUT-1), HK1, PFKP, PDK3, PKM, and LDHA at the mRNA and protein levels. We further observed reduced lactate accumulation, suggesting glycolysis was perturbed in M-I treated HNC cells. Metabolomic analyses confirmed a marked reduction in glycolytic and TCA cycle metabolites in M-I-treated cells. M-I treatment significantly downregulated mRNA and protein expression of essential enzymes involved in de novo lipogenesis, including ACLY, ACC1, FASN, SREBP1, and SCD1. Using shotgun lipidomics, we found a significant increase in lysophosphatidylcholine and phosphatidylcholine loss in M-I treated cells. Subsequently, we observed dysregulation of mitochondrial membrane potential and significant reduction of mitochondrial oxygen consumption after M-I treatment. We further observed M-I treatment induced autophagy, activated AMPK and inhibited mTOR and Akt signaling pathways and leading to apoptosis. However, blocking autophagy did not rescue the M-I-mediated alterations in lipogenesis, suggesting an independent mechanism of action. M-I treated mouse HNC MOC2 cell tumors displayed reduced Hk1, Pdk3, Fasn, and Acly expression. In conclusion, our study revealed that M-I inhibits glycolysis, lipid metabolism, induces autophagy in HNC cells and reduces tumor volume in mice. Therefore, M-I-mediated metabolic reprogramming of HNC has the potential for important therapeutic implications.
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Affiliation(s)
- Debojyoty Bandyopadhyay
- Department of Pathology, Saint Louis University, 1100 South Grand Boulevard, St. Louis, MO, 63104, USA
| | - Ellen T Tran
- Department of Pathology, Saint Louis University, 1100 South Grand Boulevard, St. Louis, MO, 63104, USA
| | - Ruchi A Patel
- Department of Pathology, Saint Louis University, 1100 South Grand Boulevard, St. Louis, MO, 63104, USA
| | - Matthew A Luetzen
- Biochemistry & Molecular Biology, Saint Louis University, St. Louis, MO, USA
| | - Kevin Cho
- Department of Chemistry and Medicine, Washington University, St. Louis, MO, USA
- Center of Mass Spectrometry and Metabolic Tracing, Washington University, St. Louis, MO, USA
| | - Leah P Shriver
- Department of Chemistry and Medicine, Washington University, St. Louis, MO, USA
- Center of Mass Spectrometry and Metabolic Tracing, Washington University, St. Louis, MO, USA
| | - Gary J Patti
- Department of Chemistry and Medicine, Washington University, St. Louis, MO, USA
- Center of Mass Spectrometry and Metabolic Tracing, Washington University, St. Louis, MO, USA
| | - Mark A Varvares
- Department of Otolaryngology, Head and Neck Surgery, Harvard Medical School, Massachusetts Eye and Ear, Boston, MA, USA
| | - David A Ford
- Biochemistry & Molecular Biology, Saint Louis University, St. Louis, MO, USA
| | - Kyle S McCommis
- Biochemistry & Molecular Biology, Saint Louis University, St. Louis, MO, USA
| | - Ratna B Ray
- Department of Pathology, Saint Louis University, 1100 South Grand Boulevard, St. Louis, MO, 63104, USA.
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Nielipińska D, Rubiak D, Pietrzyk-Brzezińska AJ, Małolepsza J, Błażewska KM, Gendaszewska-Darmach E. Stapled peptides as potential therapeutics for diabetes and other metabolic diseases. Biomed Pharmacother 2024; 180:117496. [PMID: 39362065 DOI: 10.1016/j.biopha.2024.117496] [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: 07/04/2024] [Revised: 09/10/2024] [Accepted: 09/24/2024] [Indexed: 10/05/2024] Open
Abstract
The field of peptide drug research has experienced notable progress, with stapled peptides featuring stabilized α-helical conformation, emerging as a promising field. These peptides offer enhanced stability, cellular permeability, and binding affinity and exhibit potential in the treatment of diabetes and metabolic disorders. Stapled peptides, through the disruption of protein-protein interactions, present varied functionalities encompassing agonism, antagonism, and dual-agonism. This comprehensive review offers insight into the technology of peptide stapling and targeting of crucial molecular pathways associated with glucose metabolism, insulin secretion, and food intake. Additionally, we address the challenges in developing stapled peptides, including concerns pertaining to structural stability, peptide helicity, isomer mixture, and potential side effects.
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Affiliation(s)
- Dominika Nielipińska
- Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Poland.
| | - Dominika Rubiak
- Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Poland
| | - Agnieszka J Pietrzyk-Brzezińska
- Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Poland
| | - Joanna Małolepsza
- Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Poland
| | - Katarzyna M Błażewska
- Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Poland.
| | - Edyta Gendaszewska-Darmach
- Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Poland.
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10
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Xu J, Hao J, Liao X, Shang X, Li X. SSCI: Self-Supervised Deep Learning Improves Network Structure for Cancer Driver Gene Identification. Int J Mol Sci 2024; 25:10351. [PMID: 39408682 PMCID: PMC11476395 DOI: 10.3390/ijms251910351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 09/21/2024] [Accepted: 09/23/2024] [Indexed: 10/20/2024] Open
Abstract
The pathogenesis of cancer is complex, involving abnormalities in some genes in organisms. Accurately identifying cancer genes is crucial for the early detection of cancer and personalized treatment, among other applications. Recent studies have used graph deep learning methods to identify cancer driver genes based on biological networks. However, incompleteness and the noise of the networks will weaken the performance of models. To address this, we propose a cancer driver gene identification method based on self-supervision for graph convolutional networks, which can efficiently enhance the structure of the network and further improve predictive accuracy. The reliability of SSCI is verified by the area under the receiver operating characteristic curves (AUROC), the area under the precision-recall curves (AUPRC), and the F1 score, with respective values of 0.966, 0.964, and 0.913. The results show that our method can identify cancer driver genes with strong discriminative power and biological interpretability.
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Affiliation(s)
- Jialuo Xu
- School of Computer Science, Northwestern Polytechnical University, Xi’an 710072, China; (J.X.); (J.H.); (X.L.); (X.S.)
| | - Jun Hao
- School of Computer Science, Northwestern Polytechnical University, Xi’an 710072, China; (J.X.); (J.H.); (X.L.); (X.S.)
| | - Xingyu Liao
- School of Computer Science, Northwestern Polytechnical University, Xi’an 710072, China; (J.X.); (J.H.); (X.L.); (X.S.)
| | - Xuequn Shang
- School of Computer Science, Northwestern Polytechnical University, Xi’an 710072, China; (J.X.); (J.H.); (X.L.); (X.S.)
| | - Xingyi Li
- School of Computer Science, Northwestern Polytechnical University, Xi’an 710072, China; (J.X.); (J.H.); (X.L.); (X.S.)
- Research & Development Institute of Northwestern Polytechnical University in Shenzhen, Shenzhen 518063, China
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11
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de Dios N, Riedel R, Schanton M, Balestrini P, Pérez L, Pérez-Pérez A, Etcheverry T, Casale R, Farina M, Sánchez-Margalet V, Maymó J, Varone C. Placental apoptosis increased by hypoxia inducible factor-1 stabilization is counteracted by leptin†. Biol Reprod 2024; 111:708-722. [PMID: 38924703 DOI: 10.1093/biolre/ioae095] [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: 03/23/2024] [Revised: 05/16/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
During pregnancy, apoptosis is a physiological event critical in the remodeling and aging of the placenta. Increasing evidence has pointed toward the relevance of hypoxia as modulator of trophoblast cell death. Previous reports have shown that leptin, a placental cytokine, promotes cell survival in both cell culture and placental explant models. The aim of this work is to establish the role of leptin in apoptosis under hypoxic condition in trophoblast cells. In this study, we evaluated the effect of cobalt chloride, a hypoxia mimicking agent that stabilizes the expression of hypoxia-inducible factor-1 alpha, on Swan-71 and human placental explants. Hypoxia chamber was also used to generate 2% oxygen. Apoptosis was determined by the presence of apoptotic nucleus, fragmentation of DNA and Caspase-3 and PARP-1 cleavage. The pro-apoptotic proteins BAX, BID, BAD, and BAK and the anti-apoptotic effectors BCL-2, B-cell lymphoma-extra-large, and myeloid cell leukemia-1 were also analyzed. We found that hypoxia-inducible factor-1 alpha stabilization increased the appearance of apoptotic nucleus, fragmentation of DNA, and Caspase-3 and PARP-1 cleavage. Hypoxia mimicking conditions enhanced the expression of pro-apoptotic effectors BAX, BID, BAD, and BAK. Hypoxia-inducible factor-1 alpha stabilization also downregulated the level of BCL-2, B-cell lymphoma-extra-large, and myeloid cell leukemia-1. All these apoptotic parameters changes were reversed with leptin treatment. Moreover, we showed that leptin action on apoptosis modulation involves PI3K and MAPK signaling pathways. Obtained data demonstrate that hypoxia-inducible factor-1 alpha stabilization induces apoptosis in human placenta and leptin counteracts this effect, reinforcing its role as a survival cytokine.
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Affiliation(s)
- Nataly de Dios
- Departamento de Química Biológica, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
- Universidad de Buenos Aires. CONICET. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Buenos Aires, Argentina
| | - Rodrigo Riedel
- Departamento de Química Biológica, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
- Universidad de Buenos Aires. CONICET. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Buenos Aires, Argentina
| | - Malena Schanton
- Departamento de Química Biológica, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
- Universidad de Buenos Aires. CONICET. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Buenos Aires, Argentina
| | - Paula Balestrini
- Departamento de Química Biológica, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
- Universidad de Buenos Aires. CONICET. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Buenos Aires, Argentina
| | - Luciano Pérez
- Departamento de Química Biológica, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
- Universidad de Buenos Aires. CONICET. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Buenos Aires, Argentina
| | - Antonio Pérez-Pérez
- Departamento de Bioquímica Médica y Biología Molecular. Hospital Universitario Virgen Macarena, Facultad de Medicina, Universidad de Sevilla, Sevilla, España
| | - Tomás Etcheverry
- Centro de Estudios Farmacológicos y Botánicos (CEFYBO, CONICET), Universidad de Buenos Aires. Facultad de Medicina, Buenos Aires, Argentina
| | - Roberto Casale
- Departamento Materno-Infantil, Hospital Nacional Profesor Alejandro Posadas, Buenos Aires, Argentina
| | - Mariana Farina
- Centro de Estudios Farmacológicos y Botánicos (CEFYBO, CONICET), Universidad de Buenos Aires. Facultad de Medicina, Buenos Aires, Argentina
| | - Víctor Sánchez-Margalet
- Departamento de Bioquímica Médica y Biología Molecular. Hospital Universitario Virgen Macarena, Facultad de Medicina, Universidad de Sevilla, Sevilla, España
| | - Julieta Maymó
- Departamento de Química Biológica, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
- Universidad de Buenos Aires. CONICET. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Buenos Aires, Argentina
| | - Cecilia Varone
- Departamento de Química Biológica, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
- Universidad de Buenos Aires. CONICET. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Buenos Aires, Argentina
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12
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Boucheffa S, Kheyar-Kraouche N, Djermouni M, Bettihi S, Sellal A, Cheraft N, Berboucha M, Rovellini P, Kelebek H, Tamendjari A. Extra Virgin Olive Oil's Main Components' Antioxidant Activity and in Silico Effect on AKT1. Chem Biodivers 2024; 21:e202302074. [PMID: 38923341 DOI: 10.1002/cbdv.202302074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 06/08/2024] [Accepted: 06/21/2024] [Indexed: 06/28/2024]
Abstract
The study compared the chemical composition of various olive oils from the northern Algerian province of Bejaia. The research focused on the antioxidant activities of the oil's main constituents and their ability to inhibit the AKT1 protein, which is implicated in the development of colorectal cancer. The findings revealed that all of the examined oils fell within the extra virgin olive oil (EVOO) category and exhibited a high oleic acid content, particularly for samples from wild olives. These oils include high amount of ligstroside and oleocanthal, two important phenolic compounds. Wild olive oils stand out from cultivated ones due to their higher bitterness index. In addition, these oils have the highest concentrations of α-tocopherols and the best oxidative stability. Olive oil extracts demonstrated their antioxidant properties by neutralizing DPPH and ABTS radicals and converting ferric ions (Fe3+) to ferrous ions (Fe2+) for FRAP assay. Molecular docking was applied to assess the interaction between the main compounds identified in the analyzed olive oils and the human AKT1 protein, which is involved in the genesis of colorectal cancer. The findings revealed that lutein, oleuropein aglycone, and ligstroside aglycone had the highest binding affinity for the AKT1 protein. The present study could provide the theoretical foundation for further research on the interaction between AKT1 protein and EVOO compounds.
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Affiliation(s)
- Saliha Boucheffa
- Laboratory of Applied Biochemistry, Faculty of Natural and Life Sciences, University Ferhat Abbas Sétif, 19000, Sétif, Algeria
| | - Naouel Kheyar-Kraouche
- Laboratory of Plant Biotechnology and Ethnobotany, Faculty of Nature and Life Sciences, University A/Mira University, Bejaia, 06000, Algeria
| | - Meriem Djermouni
- Laboratory of Applied Biochemistry, Faculty of Natural and Life Sciences, University Ferhat Abbas Sétif, 19000, Sétif, Algeria
| | - Sarra Bettihi
- Département de biochimie, Faculté des Sciences de la Nature et de la Vie, Université de Ferhat Abbas, 19000, Sétif, Algérie
| | - Abdelhakim Sellal
- Naturel and Life Sciences Faculty, University of Sétif 1, Sétif, Algeria
- Laboratory of Health and Environment, El Bachir El Ibrahimi University of Bordj, Bou Arreridj, Algeria
| | - Nassima Cheraft
- Laboratoire de Biochimie Appliquée, Faculté des Sciences de la Nature et de la Vie, Université de Bejaia, Bejaia, 06000, Algérie
| | - Meriem Berboucha
- Laboratoire de Biochimie Appliquée, Faculté des Sciences de la Nature et de la Vie, Université de Bejaia, Bejaia, 06000, Algérie
| | - Pierangela Rovellini
- INNOVHUB - SSIAzienda Speciale dellaCamera di Commercio di MilanoDivisione SSOG - Milano
| | - Hasim Kelebek
- Department of Food Engineering, Faculty of Engineering and Natural Sciences, Adana Alparslan Turkes Science and Technology University, 01110, Adana, Turkey
| | - Abderezak Tamendjari
- Laboratoire de Biochimie Appliquée, Faculté des Sciences de la Nature et de la Vie, Université de Bejaia, Bejaia, 06000, Algérie
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13
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Sun RX, Liu YF, Sun YS, Zhou M, Wang Y, Shi BZ, Jiang H, Li ZH. GPC3-targeted CAR-T cells expressing GLUT1 or AGK exhibit enhanced antitumor activity against hepatocellular carcinoma. Acta Pharmacol Sin 2024; 45:1937-1950. [PMID: 38750075 PMCID: PMC11336244 DOI: 10.1038/s41401-024-01287-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 04/08/2024] [Indexed: 08/22/2024]
Abstract
Chimeric antigen receptor-expressing T (CAR-T) cells induce robust antitumor responses in patients with hematologic malignancies. However, CAR-T cells exhibit only limited efficacy against solid tumors such as hepatocellular carcinoma (HCC), partially due to their limited expansion and persistence. CD8+ T cells, as key components of the adaptive immune response, play a central role in antitumor immunity. Aerobic glycolysis is the main metabolic feature of activated CD8+ T cells. In the tumor microenvironment, however, the uptake of large amounts of glucose by tumor cells and other immunosuppressive cells can impair the activation of T cells. Only when tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment have a glycolytic advantage might the effector function of T cells be activated. Glucose transporter type 1 (GLUT1) and acylglycerol kinase (AGK) can boost glycolytic metabolism and activate the effector function of CD8+ T cells, respectively. In this study, we generated GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK for the treatment of HCC. GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK specifically and effectively lysed GPC3-positive tumor cells in vitro in an antigen-dependent manner. Furthermore, GLUT1 or AGK overexpression protected CAR-T cells from apoptosis during repeated exposures to tumor cells. Compared with second-generation CAR-T cells, GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK exhibited greater CD8+ T-cell persistence in vivo and better antitumor effects in HCC allograft mouse models. Finally, we revealed that GLUT1 or AGK maintained anti-apoptosis ability in CD8+ T cells via activation of the PI3K/Akt pathway. This finding might identify a therapeutic strategy for advanced HCC.
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Affiliation(s)
- Rui-Xin Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
- Department of Laboratory Medicine, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, China
| | - Yi-Fan Liu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Yan-Sha Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Min Zhou
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
| | - Yi Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
- CARsgen Therapeutics, Shanghai, 200032, China
| | - Bi-Zhi Shi
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China
- CARsgen Therapeutics, Shanghai, 200032, China
| | - Hua Jiang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.
- CARsgen Therapeutics, Shanghai, 200032, China.
| | - Zong-Hai Li
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200032, China.
- CARsgen Therapeutics, Shanghai, 200032, China.
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14
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Adu-Amankwaah J, Adekunle AO, Tang Z, Bushi A, Tan R, Fu L, Gong Z, Ma Z, Mprah R, Ndzie Noah ML, Wowui PI, Ong'achwa Machuki J, Pan X, Li T, Sun H. Estradiol contributes to sex differences in resilience to sepsis-induced metabolic dysregulation and dysfunction in the heart via GPER-1-mediated PPARδ/NLRP3 signaling. Metabolism 2024; 156:155934. [PMID: 38762141 DOI: 10.1016/j.metabol.2024.155934] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 05/08/2024] [Indexed: 05/20/2024]
Abstract
BACKGROUND AND AIM Clinically, septic males tend to have higher mortality rates, but it is unclear if this is due to sex differences in cardiac dysfunction, possibly influenced by hormonal variations. Cardiac dysfunction significantly contributes to sepsis-related mortality, primarily influenced by metabolic imbalances. Peroxisome proliferator-activated receptor delta (PPARδ) is a key player in cardiac metabolism and its activation has been demonstrated to favor sepsis outcomes. While estradiol (E2) is abundant and beneficial in females, its impact on PPARδ-mediated metabolism in the heart with regards to sex during sepsis remains unknown. METHODS AND RESULTS Here, we unveil that while sepsis diminishes PPARδ nuclear translocation and induces metabolic dysregulation, oxidative stress, apoptosis and dysfunction in the heart thereby enhancing mortality, these effects are notably more pronounced in males than females. Mechanistic experiments employing ovariectomized(OVX) mice, E2 administration, and G protein-coupled estrogen receptor 1(GPER-1) knockout (KO) mice revealed that under lipopolysaccharide (LPS)-induced sepsis, E2 acting via GPER-1 enhances cardiac electrical activity and function, promotes PPARδ nuclear translocation, and subsequently ameliorates cardiac metabolism while mitigating oxidative stress and apoptosis in females. Furthermore, PPARδ specific activation using GW501516 in female GPER-1-/- mice reduced oxidative stress, ultimately decreasing NLRP3 expression in the heart. Remarkably, targeted GPER-1 activation using G1 in males mirrors these benefits, improving cardiac electrical activity and function, and ultimately enhancing survival rates during LPS challenge. By employing NLRP3 KO mice, we demonstrated that the targeted GPER-1 activation mitigated injury, enhanced metabolism, and reduced apoptosis in the heart of male mice via the downregulation of NLRP3. CONCLUSION Our findings collectively illuminate the sex-specific cardiac mechanisms influencing sepsis mortality, offering insights into physiological and pathological dimensions. From a pharmacological standpoint, this study introduces specific GPER-1 activation as a promising therapeutic intervention for males under septic conditions. These discoveries advance our understanding of the sex differences in sepsis-induced cardiac dysfunction and also present a novel avenue for targeted interventions with potential translational impact.
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Affiliation(s)
- Joseph Adu-Amankwaah
- Department of Physiology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | | | - Ziqing Tang
- Department of Physiology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Aisha Bushi
- School of International Education, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Rubin Tan
- Department of Physiology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Lu Fu
- Department of Physiology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Zheng Gong
- Department of Physiology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Ziyu Ma
- Department of Physiology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Richard Mprah
- Department of Physiology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | | | | | | | - Xiuhua Pan
- Department of Physiology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Tao Li
- Department of Physiology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China
| | - Hong Sun
- Department of Physiology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
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15
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Yang J, Li Y, Han X, Li T, Li D, Liu Q, Yan L, Li F, Pei X, Feng Y, Lin Z, Fu Z, Wang C, Sun Q, Li C. Targeting estrogen mediated CYP4F2/CYP4F11-20-HETE metabolic disorder decelerates tumorigenesis in ER+ breast cancer. Biochem Biophys Rep 2024; 38:101706. [PMID: 38646426 PMCID: PMC11033080 DOI: 10.1016/j.bbrep.2024.101706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 03/25/2024] [Accepted: 04/01/2024] [Indexed: 04/23/2024] Open
Abstract
Purpose As the most common subset of breast cancer (BC), estrogen receptor positive (ER+) BC accounting for 80% of cases, has become a global public health concern. The female hormone estrogen (E2) unequivocally drives ER + breast malignancies. The reasons that estrogen affects BC development has long been considered, yet further study remains to be conducted of the molecular events in the E2-estrogen receptor α (ERα) signaling pathway in ER + BC progression, especially lipid metabolism, so providing more options for tailored and individualized therapy. Our aim is to find out new targets and clinical biomarkers for ER + breast cancer treatment from the perspective of lipid metabolism. Methods Lipid metabolomics profiling was used to examine the membrane phospholipid stimulated by E2. Clinical BC samples were used to assess the association of CYP4F2, CYP4F11 expression with clinicopathological characteristics and patient outcomes. Some inhibitors of main enzymes in AA metabolism were used combined with E2 to assess roles of CYP4F2/CYP4F11 in the progression of ER + BC. CYP4F2, CYP4F11 overexpression and knockdown BC cell lines were employed to examine the effects of CYP4F2, CYP4F11 on cellular proliferation, apoptosis and tumor growth. Western blotting, qPCR, Immunohistochemical staining and flow cytometry were also conducted to determine the underlying mechanisms related to CYP4F2, CYP4F11 function. Results The activation of the CYP450 signaling pathway in arachidonic acid metabolism contributed to ER + BC tumorigenesis. In ER + BC, CYP4F2 and CYP4F11 overexpression induced by E2 could promote cancer cell proliferation and resistance to apoptosis by producing the metabolite 20-HETE and activating the antiapoptotic protein Bcl-2. CYP4F2 and CYP4F11 elevation correlates with poorer overall survival and disease-free survival in ER + BC patients. Conclusion CYP4F2, CYP4F11 and their metabolite 20-HETE could serve as effective prognostic markers and attractive therapeutic targets for novel anticancer drug development about ER + BC.
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Affiliation(s)
- Juan Yang
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300350, PR China
| | - Yin Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300350, PR China
| | - Xiao Han
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300350, PR China
| | - Tianjiao Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300350, PR China
| | - Ding Li
- Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, PR China
| | - Qiao Liu
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300350, PR China
| | - Lizhong Yan
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300350, PR China
| | - Fei Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300350, PR China
| | - Xiaolin Pei
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300350, PR China
| | - Ya Feng
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300350, PR China
| | - Zhoujun Lin
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300350, PR China
| | - Zhenkun Fu
- Department of Immunology & Wu Lien-Teh Institute & Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University & Heilongjiang Academy of Medical Science, Harbin, 150081, PR China
| | - Changjun Wang
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, 100730, PR China
| | - Qiang Sun
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, 100730, PR China
| | - Chenggang Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300350, PR China
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16
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Liang H, Zhan J, Chen Y, Xing Z, He ZNT, Liu Y, Li X, Chen Y, Li Z, Kuang C, Yang D, Yang Q. Tryptophan deficiency induced by indoleamine 2,3-dioxygenase 1 results in glucose transporter 1-dependent promotion of aerobic glycolysis in pancreatic cancer. MedComm (Beijing) 2024; 5:e555. [PMID: 38706741 PMCID: PMC11066657 DOI: 10.1002/mco2.555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 03/18/2024] [Accepted: 04/06/2024] [Indexed: 05/07/2024] Open
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1), the key enzyme in the catabolism of the essential amino acid tryptophan (Trp) through kynurenine pathway, induces immune tolerance and is considered as a critical immune checkpoint, but its impacts as a metabolism enzyme on glucose and lipid metabolism are overlooked. We aim to clarify the potential role of IDO1 in aerobic glycolysis in pancreatic cancer (PC). Analysis of database revealed the positive correlation in PC between the expressions of IDO1 and genes encoding important glycolytic enzyme hexokinase 2 (HK2), pyruvate kinase (PK), lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1). It was found that IDO1 could modulate glycolysis and glucose uptake in PC cells, Trp deficiency caused by IDO1 overexpression enhanced glucose uptake by stimulating GLUT1 translocation to the plasma membrane of PC cells. Besides, Trp deficiency caused by IDO1 overexpression suppressed the apoptosis of PC cells via promoting glycolysis, which reveals the presence of IDO1-glycolysis-apoptosis axis in PC. IDO1 inhibitors could inhibit glycolysis, promote apoptosis, and exhibit robust therapeutic efficacy when combined with GLUT1 inhibitor in PC mice. Our study reveals the function of IDO1 in the glucose metabolism of PC and provides new insights into the therapeutic strategy for PC.
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Affiliation(s)
- Heng Liang
- State Key Laboratory of Genetic EngineeringSchool of Life SciencesMOE Engineering Research Center of Gene TechnologyShanghai Engineering Research Center of Industrial MicroorganismsFudan UniversityShanghaiChina
| | - Jiani Zhan
- State Key Laboratory of Genetic EngineeringSchool of Life SciencesMOE Engineering Research Center of Gene TechnologyShanghai Engineering Research Center of Industrial MicroorganismsFudan UniversityShanghaiChina
| | - Yunqiu Chen
- State Key Laboratory of Genetic EngineeringSchool of Life SciencesMOE Engineering Research Center of Gene TechnologyShanghai Engineering Research Center of Industrial MicroorganismsFudan UniversityShanghaiChina
| | - Zikang Xing
- State Key Laboratory of Genetic EngineeringSchool of Life SciencesMOE Engineering Research Center of Gene TechnologyShanghai Engineering Research Center of Industrial MicroorganismsFudan UniversityShanghaiChina
| | - Zhen Ning Tony He
- State Key Laboratory of Genetic EngineeringSchool of Life SciencesMOE Engineering Research Center of Gene TechnologyShanghai Engineering Research Center of Industrial MicroorganismsFudan UniversityShanghaiChina
| | - Yuying Liu
- State Key Laboratory of Genetic EngineeringSchool of Life SciencesMOE Engineering Research Center of Gene TechnologyShanghai Engineering Research Center of Industrial MicroorganismsFudan UniversityShanghaiChina
| | - Xuewen Li
- State Key Laboratory of Genetic EngineeringSchool of Life SciencesMOE Engineering Research Center of Gene TechnologyShanghai Engineering Research Center of Industrial MicroorganismsFudan UniversityShanghaiChina
| | - Yijia Chen
- State Key Laboratory of Genetic EngineeringSchool of Life SciencesMOE Engineering Research Center of Gene TechnologyShanghai Engineering Research Center of Industrial MicroorganismsFudan UniversityShanghaiChina
| | - Zhiyao Li
- State Key Laboratory of Genetic EngineeringSchool of Life SciencesMOE Engineering Research Center of Gene TechnologyShanghai Engineering Research Center of Industrial MicroorganismsFudan UniversityShanghaiChina
| | - Chunxiang Kuang
- Shanghai Key Lab of Chemical Assessment and SustainabilitySchool of Chemical Science and EngineeringTongji UniversityShanghaiChina
| | - Dan Yang
- Department of OrthopedicsShanghai Children's HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Qing Yang
- State Key Laboratory of Genetic EngineeringSchool of Life SciencesMOE Engineering Research Center of Gene TechnologyShanghai Engineering Research Center of Industrial MicroorganismsFudan UniversityShanghaiChina
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17
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Hou Z, Wu C, Tang J, Liu S, Li L. CLSPN actives Wnt/β-catenin signaling to facilitate glycolysis and cell proliferation in oral squamous cell carcinoma. Exp Cell Res 2024; 435:113935. [PMID: 38237848 DOI: 10.1016/j.yexcr.2024.113935] [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: 10/19/2023] [Revised: 01/01/2024] [Accepted: 01/15/2024] [Indexed: 02/04/2024]
Abstract
OBJECTIVE Oral squamous cell carcinoma (OSCC) is a common malignancy with a poor prognosis. This study aimed to determine the influence and underlying mechanisms of CLSPN on OSCC. METHODS CLSPN expression was tested using quantitative real-time polymerase chain reaction, immunohistochemistry, and western blotting. Flow cytometry, cell counting kit, and colony formation assays were performed to determine OSCC cell apoptosis, viability, and proliferation, respectively. In OSCC cells, the extracellular acidification rate (ECAR), oxygen consumption rate (OCR), glucose uptake, and lactate production were determined using the corresponding kits. Changes in the protein levels of HK2, PKM2, LDHA, Wnt3a, and β-catenin were assessed using western blotting. RESULTS CLSPN expression was increased in OSCC tissues. Overexpression of CLSPN in HSC-2 cells promoted cell proliferation, increased the levels of ECAR, glucose uptake, and lactate production, and increased the protein levels of HK2, PKM2, LDHA, Wnt3a, and β-catenin, but inhibited OCR levels and apoptosis. The knockdown of CLSPN in CAL27 cells resulted in the opposite results. Moreover, the effects of CLSPN overexpression on glycolysis and OSCC cell proliferation were reversed by Wnt3a knockdown. In vivo, knockdown of CLSPN restrained tumor growth, glycolysis, and the activation of Wnt/β-catenin signaling. CONCLUSION CLSPN promoted glycolysis and OSCC cell proliferation, and reduced apoptosis, which was achieved by the activation of Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Zeyu Hou
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Chenzhou Wu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Jinru Tang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Shaohua Liu
- Department of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
| | - Longjiang Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
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18
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Plehn S, Wagle S, Rupasinghe HV. Chaga mushroom triterpenoids as adjuncts to minimally invasive cancer therapies: A review. Curr Res Toxicol 2023; 5:100137. [PMID: 38046279 PMCID: PMC10692653 DOI: 10.1016/j.crtox.2023.100137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 10/13/2023] [Accepted: 11/14/2023] [Indexed: 12/05/2023] Open
Abstract
Cancer has become the second leading cause of death in the world. Integrative cancer therapy management is continuously evolving to enhance treatment outcomes. Chaga mushroom (Inonotus obliquus) is a parasitic fungus acclaimed to contain pharmaceutical and nutraceutical value in the fight against cancer. In particular, triterpenoid constituents derived from Chaga mushrooms have been recognized for their anti-cancer activity after distinguished cytotoxicity was repeatedly observed in cancer cells treated in vitro with lipophilic fractions of extract compared to aqueous ones. Studies that investigate the anti-cancer activity of Chaga mushroom triterpenoids are reviewed in this article to determine which cancer cell lines demonstrate the greatest susceptibility to them while highlighting the structure-activity relationships that are involved. Triterpenoid supplementation as an adjunct to cancer treatment may be a viable option as inotodiol and 3-β-22 α-dihydroxylanosta-8, 25-diene-24-one have been shown to exhibit anti-cancer activity similar to that of conventional drugs. Advances in addressing bioavailability challenges are also included in this review as studies include in vivo components.
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Affiliation(s)
- Selina Plehn
- Department of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia, B2N 5E3, Canada
| | - Sajeev Wagle
- Department of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia, B2N 5E3, Canada
| | - H.P. Vasantha Rupasinghe
- Department of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia, B2N 5E3, Canada
- Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 4H7, Canada
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19
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Iqbal MA, Siddiqui S, Smith K, Singh P, Kumar B, Chouaib S, Chandrasekaran S. Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance. iScience 2023; 26:108059. [PMID: 37854701 PMCID: PMC10579441 DOI: 10.1016/j.isci.2023.108059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 07/17/2023] [Accepted: 09/22/2023] [Indexed: 10/20/2023] Open
Abstract
Extensive metabolic heterogeneity in breast cancers has limited the deployment of metabolic therapies. To enable patient stratification, we studied the metabolic landscape in breast cancers (∼3000 patients combined) and identified three subtypes with increasing degrees of metabolic deregulation. Subtype M1 was found to be dependent on bile-acid biosynthesis, whereas M2 showed reliance on methionine pathway, and M3 engaged fatty-acid, nucleotide, and glucose metabolism. The extent of metabolic alterations correlated strongly with tumor aggressiveness and patient outcome. This pattern was reproducible in independent datasets and using in vivo tumor metabolite data. Using machine-learning, we identified robust and generalizable signatures of metabolic subtypes in tumors and cell lines. Experimental inhibition of metabolic pathways in cell lines representing metabolic subtypes revealed subtype-specific sensitivity, therapeutically relevant drugs, and promising combination therapies. Taken together, metabolic stratification of breast cancers can thus aid in predicting patient outcome and designing precision therapies.
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Affiliation(s)
- Mohammad A. Iqbal
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
- College of Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | | | - Kirk Smith
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Prithvi Singh
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia (A Central University), New Delhi, India
| | - Bhupender Kumar
- Department of Microbiology, Swami Shraddhanand College, University of Delhi, New Delhi, Delhi, India
| | - Salem Chouaib
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates
- College of Medicine, Gulf Medical University, Ajman, United Arab Emirates
- INSERM UMR 1186, Gustave Roussy, EPHE, Faculty of Medicine, University of Paris-Saclay, Villejuif, France
| | - Sriram Chandrasekaran
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Program in Chemical Biology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
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20
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Masuda-Kuroki K, Alimohammadi S, Di Nardo A. The Role of Sphingolipids and Sphingosine-1-phosphate-Sphingosine-1-phosphate-receptor Signaling in Psoriasis. Cells 2023; 12:2352. [PMID: 37830566 PMCID: PMC10571972 DOI: 10.3390/cells12192352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 09/21/2023] [Accepted: 09/25/2023] [Indexed: 10/14/2023] Open
Abstract
Psoriasis is a long-lasting skin condition characterized by redness and thick silver scales on the skin's surface. It involves various skin cells, including keratinocytes, dendritic cells, T lymphocytes, and neutrophils. The treatments for psoriasis range from topical to systemic therapies, but they only alleviate the symptoms and do not provide a fundamental cure. Moreover, systemic treatments have the disadvantage of suppressing the entire body's immune system. Therefore, a new treatment strategy with minimal impact on the immune system is required. Recent studies have shown that sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate (S1P), play a significant role in psoriasis. Specific S1P-S1P-receptor (S1PR) signaling pathways have been identified as crucial to psoriasis inflammation. Based on these findings, S1PR modulators have been investigated and have been found to improve psoriasis inflammation. This review will discuss the metabolic pathways of sphingolipids, the individual functions of these metabolites, and their potential as a new therapeutic approach to psoriasis.
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Affiliation(s)
| | | | - Anna Di Nardo
- Department of Dermatology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (K.M.-K.); (S.A.)
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21
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Bishayee K, Lee SH, Park YS. The Illustration of Altered Glucose Dependency in Drug-Resistant Cancer Cells. Int J Mol Sci 2023; 24:13928. [PMID: 37762231 PMCID: PMC10530558 DOI: 10.3390/ijms241813928] [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: 08/11/2023] [Revised: 09/07/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
A chemotherapeutic approach is crucial in malignancy management, which is often challenging due to the development of chemoresistance. Over time, chemo-resistant cancer cells rapidly repopulate and metastasize, increasing the recurrence rate in cancer patients. Targeting these destined cancer cells is more troublesome for clinicians, as they share biology and molecular cross-talks with normal cells. However, the recent insights into the metabolic profiles of chemo-resistant cancer cells surprisingly illustrated the activation of distinct pathways compared with chemo-sensitive or primary cancer cells. These distinct metabolic dynamics are vital and contribute to the shift from chemo-sensitivity to chemo-resistance in cancer. This review will discuss the important metabolic alterations in cancer cells that lead to drug resistance.
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Affiliation(s)
- Kausik Bishayee
- Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| | | | - Yong Soo Park
- Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
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22
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Minafra AR, Rafii P, Mossner S, Bazgir F, Floss DM, Moll JM, Scheller J. Synthetic receptor platform to identify loss-of-function single nucleotide variants and designed mutants in the death receptor Fas/CD95. J Biol Chem 2023; 299:104989. [PMID: 37392849 PMCID: PMC10413154 DOI: 10.1016/j.jbc.2023.104989] [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: 12/21/2022] [Revised: 05/17/2023] [Accepted: 06/12/2023] [Indexed: 07/03/2023] Open
Abstract
Synthetic biology has emerged as a useful technology for studying cytokine signal transduction. Recently, we described fully synthetic cytokine receptors to phenocopy trimeric receptors such as the death receptor Fas/CD95. Using a nanobody as an extracellular-binding domain for mCherry fused to the natural receptor's transmembrane and intracellular domain, trimeric mCherry ligands were able to induce cell death. Among the 17,889 single nucleotide variants in the SNP database for Fas, 337 represent missense mutations that functionally remained largely uncharacterized. Here, we developed a workflow for the Fas synthetic cytokine receptor system to functionally characterize missense SNPs within the transmembrane and intracellular domain of Fas. To validate our system, we selected five functionally assigned loss-of-function (LOF) polymorphisms and included 15 additional unassigned SNPs. Moreover, based on structural data, 15 gain-of-function or LOF candidate mutations were additionally selected. All 35 nucleotide variants were functionally investigated through cellular proliferation, apoptosis and caspases 3 and 7 cleavage assays. Collectively, our results showed that 30 variants resulted in partial or complete LOF, while five lead to a gain-of-function. In conclusion, we demonstrated that synthetic cytokine receptors are a suitable tool for functional SNPs/mutations characterization in a structured workflow.
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Affiliation(s)
- Anna Rita Minafra
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Puyan Rafii
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Sofie Mossner
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Farhad Bazgir
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Doreen M Floss
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Jens M Moll
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; PROvendis GmbH, Muelheim an der Ruhr, Germany
| | - Jürgen Scheller
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
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23
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Qiao X, Zhu L, Song R, Shang C, Guo Y. A novel oncogene trigger transposable element derived-1 promotes oral squamous cell carcinoma progression via evoking immune inhibition. Mol Carcinog 2023. [PMID: 37144838 DOI: 10.1002/mc.23557] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 04/22/2023] [Accepted: 04/25/2023] [Indexed: 05/06/2023]
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common head and neck squamous cell carcinomas (HNSCC) globally. Its incidence rate is rapidly increasing, and its 5-year survival rate remains at 50%, despite advances in medical science. Trigger transposable element-derived 1 (TIGD1) has been found to be upregulated in various cancer types. However, its biological function in OSCC requires further investigation. We searched the Cancer Genome Atlas database using CIBERSORT and TIMER 2.0 to predict the significance of TIGD1 and evaluate its effect on immune cell infiltration. Gene set enrichment analysis was performed to determine the biological functions of TIGD1. Gain/loss of function techniques were used to explore the biological behavior of TIGD1 in Cal27 and HSC4 cells. Finally, flow cytometry was used to detect dendritic cell markers in an OSCC and dendritic cell co-culture model. Our results show that TIGD1 is upregulated significantly in OSCC and is closely associated with tumor progression and prognosis. TIGD1 functions as an oncogene by increasing cells proliferation, inhibiting apoptosis, promoting cell invasion and migration. TIGD1 is also involved in tumor immune cell infiltration. Its overexpression can inhibit dendritic cell maturation, leading to immune suppression and tumor progression. High TIGD1 expression, which promotes OSCC progression, might be related to decreased dendritic cell maturation and activation. These findings suggest that TIGD1-specific small interfering RNA synthesized in vitro could be a new target for OSCC immunotherapy.
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Affiliation(s)
- Xue Qiao
- Department of Central Laboratory, Liaoning Provincial Key Laboratory of Oral Disease, School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China
- Department of Oral Biology, Liaoning Provincial Key Laboratory of Oral Disease, School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China
| | - Li Zhu
- Department of Central Laboratory, Liaoning Provincial Key Laboratory of Oral Disease, School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China
| | - Rongbo Song
- Department of Central Laboratory, Liaoning Provincial Key Laboratory of Oral Disease, School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China
| | - Chao Shang
- Department of Neurobiology, China Medical University, Shenyang, Liaoning, China
| | - Yan Guo
- Department of Central Laboratory, Liaoning Provincial Key Laboratory of Oral Disease, School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China
- Department of Oral Biology, Liaoning Provincial Key Laboratory of Oral Disease, School and Hospital of Stomatology, China Medical University, Shenyang, Liaoning, China
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24
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Niu N, Ye J, Hu Z, Zhang J, Wang Y. Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis. Int J Mol Sci 2023; 24:ijms24087076. [PMID: 37108242 PMCID: PMC10139088 DOI: 10.3390/ijms24087076] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/23/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
One important feature of tumour development is the regulatory role of metabolic plasticity in maintaining the balance of mitochondrial oxidative phosphorylation and glycolysis in cancer cells. In recent years, the transition and/or function of metabolic phenotypes between mitochondrial oxidative phosphorylation and glycolysis in tumour cells have been extensively studied. In this review, we aimed to elucidate the characteristics of metabolic plasticity (emphasizing their effects, such as immune escape, angiogenesis migration, invasiveness, heterogeneity, adhesion, and phenotypic properties of cancers, among others) on tumour progression, including the initiation and progression phases. Thus, this article provides an overall understanding of the influence of abnormal metabolic remodeling on malignant proliferation and pathophysiological changes in carcinoma.
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Affiliation(s)
- Nan Niu
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
- College of Physics and Optoelectronic Engineering, Canghai Campus of Shenzhen University, Shenzhen 518060, China
| | - Jinfeng Ye
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
| | - Zhangli Hu
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
| | - Junbin Zhang
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
| | - Yun Wang
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
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25
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Zheng Z, Chen J, Chen X, Huang L, Xie W, Lin Q, Li X, Wong K. Enabling Single-Cell Drug Response Annotations from Bulk RNA-Seq Using SCAD. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2204113. [PMID: 36762572 PMCID: PMC10104628 DOI: 10.1002/advs.202204113] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 12/09/2022] [Indexed: 06/18/2023]
Abstract
The single-cell RNA sequencing (scRNA-seq) quantifies the gene expression of individual cells, while the bulk RNA sequencing (bulk RNA-seq) characterizes the mixed transcriptome of cells. The inference of drug sensitivities for individual cells can provide new insights to understand the mechanism of anti-cancer response heterogeneity and drug resistance at the cellular resolution. However, pharmacogenomic information related to their corresponding scRNA-Seq is often limited. Therefore, a transfer learning model is proposed to infer the drug sensitivities at single-cell level. This framework learns bulk transcriptome profiles and pharmacogenomics information from population cell lines in a large public dataset and transfers the knowledge to infer drug efficacy of individual cells. The results suggest that it is suitable to learn knowledge from pre-clinical cell lines to infer pre-existing cell subpopulations with different drug sensitivities prior to drug exposure. In addition, the model offers a new perspective on drug combinations. It is observed that drug-resistant subpopulation can be sensitive to other drugs (e.g., a subset of JHU006 is Vorinostat-resistant while Gefitinib-sensitive); such finding corroborates the previously reported drug combination (Gefitinib + Vorinostat) strategy in several cancer types. The identified drug sensitivity biomarkers reveal insights into the tumor heterogeneity and treatment at cellular resolution.
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Affiliation(s)
- Zetian Zheng
- Department of Computer ScienceCity University of Hong KongKowloonHong Kong
| | - Junyi Chen
- The Laboratory of Data Discovery for Health (D²4H), Hong Kong Science ParkNew TerritoriesHong Kong
| | - Xingjian Chen
- Department of Computer ScienceCity University of Hong KongKowloonHong Kong
| | - Lei Huang
- Department of Computer ScienceCity University of Hong KongKowloonHong Kong
| | - Weidun Xie
- Department of Computer ScienceCity University of Hong KongKowloonHong Kong
| | - Qiuzhen Lin
- College of Computer Science and Software Engineering, Shenzhen UniversityShenzhenChina
| | - Xiangtao Li
- School of Artificial IntelligenceJilin UniversityJilinChina
| | - Ka‐Chun Wong
- Department of Computer ScienceCity University of Hong KongKowloonHong Kong
- Shenzhen Research InstituteCity University of Hong KongShenzhenChina
- Hong Kong Institute for Data ScienceCity University of Hong KongKowloonHong Kong
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26
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Cui ZH, Ma YD, Wang YC, Liu H, Song JW, Zhang LX, Guo WJ, Zhang XQ, Tu SS, Yuan DZ, Zhang JH, Nie L, Yue LM. PCSK9 involves in the high-fat diet-induced abnormal testicular function of male mice. Reproduction 2023; 165:457-474. [PMID: 36745023 DOI: 10.1530/rep-22-0216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 02/06/2023] [Indexed: 02/07/2023]
Abstract
In brief Impaired spermatogenesis resulting from disturbed cholesterol metabolism due to intake of high-fat diet (HFD) has been widely recognized, however, the role of preprotein invertase subtilin 9 (PCSK9), which is a negative regulator of cholesterol metabolism, has never been reported. This study aims to reveal the role of PCSK9 on spermatogenesis induced by HFD in mice. Abstract Long-term consumption of a high-fat diet (HFD) is an important factor that leads to impaired spermatogenesis exhibiting poor sperm quantity and quality. However, the mechanism of this is yet to be elucidated. Disrupted cholesterol homeostasis is one of many crucial pathological factors which could contribute to impaired spermatogenesis. As a negative regulator of cholesterol metabolism, preprotein invertase subtilin 9 (PCSK9) mediates low density lipoprotein receptor (LDLR) degradation to the lysosome, thereby reducing the expression of LDLR on the cell membrane and increasing serum low-density lipoprotein cholesterol level, resulting in lipid metabolism disorders. Here, we aim to study whether PCSK9 is a pathological factor for impaired spermatogenesis induced by HFD and the underlying mechanism. To meet the purpose of our study, we utilized wild-type C57BL/6 male mice and PCSK9 knockout mice with same background as experimental subjects and alirocumab, a PCSK9 inhibitor, was used for treatment. Results indicated that HFD induced higher PCSK9 expression in serum, liver, and testes, and serum PCSK9 is negatively correlated with spermatogenesis, while both PCSK9 inhibitor treatment and PCSK9 knockout methodologies ameliorated impaired lipid metabolism and spermatogenesis in mice fed a HFD. This could be due to the overexpression of PCSK9 induced by HFD leading to dyslipidemia, resulting in testicular lipotoxicity, thus activating the Bcl-2-Bax-Caspase3 apoptosis signaling pathway in testes, particularly in Leydig cells. Our study demonstrates that PCSK9 is an important pathological factor in the dysfunction of spermatogenesis in mice induced by HFD. This finding could provide innovative ideas for the diagnosis and treatment of male infertility.
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Affiliation(s)
- Zhi-Hui Cui
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China.,Department of Growth and Reproduction, Group of Skeletal, Mineral, and Gonadal Endocrinology, Rigshospitalet, Copenhagen, Denmark
| | - Yong-Dan Ma
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Yi-Cheng Wang
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Huan Liu
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Jia-Wei Song
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Li-Xue Zhang
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Wen-Jing Guo
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Xue-Qin Zhang
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Sha-Sha Tu
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Dong-Zhi Yuan
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Jin-Hu Zhang
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Li Nie
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China
| | - Li-Min Yue
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China.,Reproductive Endocrinology and Regulation Joint Laboratory, West China Second Hospital, Sichuan University, Chengdu, China
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Cui W, Wen Q, Lurong D, Wu Y, Gao S, Li J, Li N, Xu C. Multi-omics reveals Bifidobacterium longum CECT7894 alleviate food allergy by regulating the Sphingolipid metabolism pathway. FOOD BIOSCI 2023. [DOI: 10.1016/j.fbio.2023.102622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
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28
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Chen Q, Chen S, Wang J, Zhao Y, Ye X, Fu Y, Liu Y. Construction and validation of a hypoxia-related risk signature identified EXO1 as a prognostic biomarker based on 12 genes in lung adenocarcinoma. Aging (Albany NY) 2023; 15:2293-2307. [PMID: 36971680 PMCID: PMC10085621 DOI: 10.18632/aging.204613] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Accepted: 03/15/2023] [Indexed: 03/29/2023]
Abstract
BACKGROUND Increasing evidence has demonstrated the clinical importance of hypoxia and its related factors in lung adenocarcinoma (LUAD). METHODS RNA-seq datasets from The Cancer Genome Atlas (TCGA) were analyzed using the differentially expressed genes in hypoxia pathway by the Least Absolute Shrinkage and Selection Operator (LASSO) model. Applying gene ontology (GO) and gene set enrichment analysis (GSEA), a risk signature associated with the survival of LUAD patients was constructed between LUAD and normal tissue. RESULTS In total, 166 hypoxia-related genes were identified. Based on the LASSO Cox regression, 12 genes were selected for the development of the risk signature. Then, we designed an OS-associated nomogram that included the risk score and clinical factors. The concordance index of the nomogram was 0.724. ROC curve showed better predictive ability using the nomogram (AUC = 0.811 for 5-year OS). Finally, the expressions of the 12 genes were validated in two external datasets and EXO1 was recognized as a potential biomarker in the progression of LUAD patients. CONCLUSIONS Overall, our data suggested that hypoxia is associated with the prognosis, and EXO1 acted as a promising biomarker in LUAD.
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Zong Q, Bundkirchen K, Neunaber C, Noack S. Are the Properties of Bone Marrow-Derived Mesenchymal Stem Cells Influenced by Overweight and Obesity? Int J Mol Sci 2023; 24:ijms24054831. [PMID: 36902259 PMCID: PMC10003331 DOI: 10.3390/ijms24054831] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 02/22/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BMSCs) are promising candidates for cell-based therapies. Growing evidence has indicated that overweight/obesity can change the bone marrow microenvironment, which affects some properties of BMSCs. As the overweight/obese population rapidly increases, they will inevitably become a potential source of BMSCs for clinical application, especially when receiving autologous BMSC transplantation. Given this situation, the quality control of these cells has become particularly important. Therefore, it is urgent to characterize BMSCs isolated from overweight/obese bone marrow environments. In this review, we summarize the evidence of the effects of overweight/obesity on the biological properties of BMSCs derived from humans and animals, including proliferation, clonogenicity, surface antigen expression, senescence, apoptosis, and trilineage differentiation, as well as the underlying mechanisms. Overall, the conclusions of existing studies are not consistent. Most studies demonstrate that overweight/obesity can influence one or more characteristics of BMSCs, while the involved mechanisms are still unclear. Moreover, insufficient evidence proves that weight loss or other interventions can rescue these qualities to baseline status. Thus, further research should address these issues and prioritize developing methods to improve functions of overweight- or obesity-derived BMSCs.
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Michaelis V, Kasper S, Naperkowski L, Pusse J, Thiel A, Ebert F, Aschner M, Schwerdtle T, Haase H, Bornhorst J. The Impact of Zinc on Manganese Bioavailability and Cytotoxicity in HepG2 Cells. Mol Nutr Food Res 2023; 67:e2200283. [PMID: 36683243 DOI: 10.1002/mnfr.202200283] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
SCOPE Despite their essentiality, several studies have shown that either manganese (Mn) or zinc (Zn) overexposure may lead to detrimental health effects. Although Mn is transported by some of the SLC family transporters that translocate Zn, the role of Zn in hepatocellular Mn transport and Mn-induced toxicity have yet to be fully characterized. METHODS AND RESULTS The human hepatoma cell line, HepG2, is utilized. Total cellular Mn and Zn amounts are determined after cells are treated with Zn 2 or 24 h prior to Mn incubation for additional 24 h with inductively coupled plasma-based spectrometry and labile Zn is assessed with the fluorescent probe FluoZin-3. Furthermore, mRNA expression of genes involved in metal homeostasis, and mechanistic endpoints associated with Mn-induced cytotoxicity are addressed. These results suggest that Zn protects against Mn-induced cytotoxicity and impacts Mn bioavailability to a great extent when cells are preincubated with higher Zn concentrations for longer duration as characterized by decreased activation of caspase-3 as well as lactate dehydrogenase (LDH) release. CONCLUSIONS Zn protects against Mn-induced cytotoxicity in HepG2 cells possibly due to decreased Mn bioavailability. Additionally, mRNA expression of metal homeostasis-related genes indicates possible underlying pathways that should to be addressed in future studies.
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Affiliation(s)
- Vivien Michaelis
- Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstraße 20, 42119, Wuppertal, Germany
| | - Silja Kasper
- Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstraße 20, 42119, Wuppertal, Germany
| | - Lisa Naperkowski
- Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstraße 20, 42119, Wuppertal, Germany
| | - Jan Pusse
- Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstraße 20, 42119, Wuppertal, Germany
| | - Alicia Thiel
- Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstraße 20, 42119, Wuppertal, Germany
| | - Franziska Ebert
- Department of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Michael Aschner
- Department of Molecular Pharmacology, Neuroscience, and Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
| | - Tanja Schwerdtle
- Department of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
- TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558), Berlin-Potsdam-Jena-Wuppertal, 14558, Nuthetal, Germany
- German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Straße 8-10, 10589, Berlin, Germany
| | - Hajo Haase
- TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558), Berlin-Potsdam-Jena-Wuppertal, 14558, Nuthetal, Germany
- Department of Food Chemistry and Toxicology, Berlin Institute of Technology, Gustav-Meyer-Allee 25, 13355, Berlin, Germany
| | - Julia Bornhorst
- Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstraße 20, 42119, Wuppertal, Germany
- TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly (FOR 2558), Berlin-Potsdam-Jena-Wuppertal, 14558, Nuthetal, Germany
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The Role of Reprogrammed Glucose Metabolism in Cancer. Metabolites 2023; 13:metabo13030345. [PMID: 36984785 PMCID: PMC10051753 DOI: 10.3390/metabo13030345] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/19/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Cancer cells reprogram their metabolism to meet biosynthetic needs and to adapt to various microenvironments. Accelerated glycolysis offers proliferative benefits for malignant cells by generating glycolytic products that move into branched pathways to synthesize proteins, fatty acids, nucleotides, and lipids. Notably, reprogrammed glucose metabolism and its associated events support the hallmark features of cancer such as sustained cell proliferation, hijacked apoptosis, invasion, metastasis, and angiogenesis. Overproduced enzymes involved in the committed steps of glycolysis (hexokinase, phosphofructokinase-1, and pyruvate kinase) are promising pharmacological targets for cancer therapeutics. In this review, we summarize the role of reprogrammed glucose metabolism in cancer cells and how it can be manipulated for anti-cancer strategies.
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Fang H, Chen Z, Liu Y, Zhang T, Chang J, Li Z, Zhang L, Sui J, Ru J, Gu Y, Hua X. Discovery of Aryloxy-, Arylthio-, and Arylamino-Containing Acethydrazides as Fungicidal Agents. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:920-933. [PMID: 36534960 DOI: 10.1021/acs.jafc.2c06691] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
The development of new green fungicides is an effective way to solve the resistance of agricultural pathogens and plays an important role in promoting high-quality and sustainable development of modern agriculture. In this project, a series of aryloxy-, arylthio-, and arylamino-containing acethydrazide derivatives were designed, synthesized, and characterized by 1H nuclear magnetic resonance (NMR), 13C NMR, and high-resolution mass spectrometry (HRMS). The fungicidal bioassays indicated that some compounds showed excellent and broad-spectrum fungicidal activity, and the structure-activity relationship was discussed. The in vivo fungicidal activity demonstrated that compounds C4 and D8 exhibited good preventative effects against Fusarium graminearum infecting wheat leaves, of which the preventative activity of compound D8 was almost equal to that of the positive agents. Transmission electron microscopy (TEM) observation revealed that the plasma membrane in the C4-treated F. graminearum hyphal cells was severely contracted and separated with the cell wall, coupling with the visible lysosomes and the disappeared cytoplasm and organelles, which may be the reasons for the shriveled and even ruptured hyphae observed by scanning electron microscopy (SEM). Subsequently, transcriptomics and metabolomics were performed to further elucidate the fungicidal mechanism. The regulatory networks of differential genes and metabolites in plasma membrane-related sphingolipid metabolism, linoleic acid metabolism, α-linoleic acid metabolism, and arachidonic acid metabolism were constructed and elaborated. Additionally, preliminary investigation of seeding growth suggested that compounds C4 and D8 may have different degrees of influence on the growth indicators of wheat seedlings; however, this effect may be negligible as the plant grows.
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Affiliation(s)
- Hongbin Fang
- College of Agricultural Science and Engineering, Liaocheng University, No. 1, Hu'nan Road, Dongchangfu District, Liaocheng 252000, P. R. China
| | - Zhanfang Chen
- College of Agricultural Science and Engineering, Liaocheng University, No. 1, Hu'nan Road, Dongchangfu District, Liaocheng 252000, P. R. China
| | - Yang Liu
- College of Agricultural Science and Engineering, Liaocheng University, No. 1, Hu'nan Road, Dongchangfu District, Liaocheng 252000, P. R. China
| | - Tiancheng Zhang
- College of Agricultural Science and Engineering, Liaocheng University, No. 1, Hu'nan Road, Dongchangfu District, Liaocheng 252000, P. R. China
| | - Jing Chang
- College of Agricultural Science and Engineering, Liaocheng University, No. 1, Hu'nan Road, Dongchangfu District, Liaocheng 252000, P. R. China
| | - Zizheng Li
- College of Agricultural Science and Engineering, Liaocheng University, No. 1, Hu'nan Road, Dongchangfu District, Liaocheng 252000, P. R. China
| | - Lingxiao Zhang
- College of Agricultural Science and Engineering, Liaocheng University, No. 1, Hu'nan Road, Dongchangfu District, Liaocheng 252000, P. R. China
| | - Junkang Sui
- College of Agricultural Science and Engineering, Liaocheng University, No. 1, Hu'nan Road, Dongchangfu District, Liaocheng 252000, P. R. China
| | - Jing Ru
- College of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng 252000, P. R. China
| | - Yucheng Gu
- Jealott's Hill International Research Centre, Syngenta Ltd., Bracknell RG42 6EY, U.K
| | - Xuewen Hua
- College of Agricultural Science and Engineering, Liaocheng University, No. 1, Hu'nan Road, Dongchangfu District, Liaocheng 252000, P. R. China
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Yan C, Li Q, Sun Q, Yang L, Liu X, Zhao Y, Shi M, Li X, Luo K. Promising Nanomedicines of Shikonin for Cancer Therapy. Int J Nanomedicine 2023; 18:1195-1218. [PMID: 36926681 PMCID: PMC10013574 DOI: 10.2147/ijn.s401570] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/15/2023] [Indexed: 03/18/2023] Open
Abstract
Malignant tumor, the leading cause of death worldwide, poses a serious threat to human health. For decades, natural product has been proven to be an essential source for novel anticancer drug discovery. Shikonin (SHK), a natural molecule separated from the root of Lithospermum erythrorhizon, shows great potential in anticancer therapy. However, its further clinical application is significantly restricted by poor bioavailability, adverse effects, and non-selective toxicity. With the development of nanotechnology, nano drug delivery systems have emerged as promising strategies to improve bioavailability and enhance the therapeutic efficacy of drugs. To overcome the shortcoming of SHK, various nano drug delivery systems such as liposomes, polymeric micelles, nanoparticles, nanogels, and nanoemulsions, were developed to achieve efficient delivery for enhanced antitumor effects. Herein, this review summarizes the anticancer pharmacological activities and pharmacokinetics of SHK. Additionally, the latest progress of SHK nanomedicines in cancer therapy is outlined, focusing on long circulation, tumor targeting ability, tumor microenvironment responsive drug release, and nanosystem-mediated combination therapy. Finally, the challenges and prospects of SHK nanomedicines in the future clinical application are spotlighted.
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Affiliation(s)
- Chunmei Yan
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Qiuxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Qiang Sun
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People's Republic of China
| | - Lu Yang
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Xing Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Yuxin Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Mingyi Shi
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Xiaofang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Kaipei Luo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
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Hu X, Guo B, Sun T, Wang W. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3. Open Med (Wars) 2023; 18:20230635. [PMID: 37069941 PMCID: PMC10105522 DOI: 10.1515/med-2023-0635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 12/05/2022] [Accepted: 12/11/2022] [Indexed: 04/19/2023] Open
Abstract
Considering the role of glycolysis inhibition as a novel therapeutic strategy for cancer, including breast cancer (BC), we wondered whether glycolysis could affect BC progression by regulating transmembrane O-mannosyltransferase-targeting cadherins 3 (TMTC3). Following the intervention, lactic acid production in BC cells was monitored, and viability, proliferation, and apoptosis assays were performed. The expressions of TMTC3 and endoplasmic reticulum (ER) stress- and apoptosis-related factors Caspase-12, C/EBP homologous protein (CHOP), glucose-regulated protein 78 (GRP78), B-cell lymphoma-2 (Bcl-2), and Bcl-2 associated X (Bax) were quantified. TMTC3 was lowly expressed in BC tissue and cell. The promotion of glycolysis via glucose represses TMTC3 expression and apoptosis yet enhances lactic acid production and growth of BC cell, along with promoted levels of Caspase-12, CHOP, GRP78, and Bcl-2 yet repressed level of Bax, while the contrary results were evidenced after 2-deoxyglycouse intervention. Overexpressed TMTC3 additionally abrogated the effects of glycolysis on increasing the viability and proliferation yet inhibiting the apoptosis of BC cells, with the increased expressions of Caspase-12, CHOP, and GRP78, and Bcl-2 yet decreased level of Bax. Collectively, inhibiting glycolysis restrained the growth and attenuated the ER stress of BC cell by regulating TMTC3.
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Affiliation(s)
- Xue Hu
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun City, Jilin Province, 130033, China
| | - Baoliang Guo
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin City, Heilongjiang Province, China
| | - Tong Sun
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun City, Jilin Province, 130033, China
| | - Wan Wang
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, No. 126 Xiantai
Avenue, Nanguan District, Changchun City, Jilin Province, 130033, China
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Pradhan V, Salahuddin, Kumar R, Mazumder A, Abdullah MM, Shahar Yar M, Ahsan MJ, Ullah Z. Molecular Target Interactions of Quinoline Derivatives as Anticancer Agents: A Review. Chem Biol Drug Des 2022; 101:977-997. [PMID: 36533867 DOI: 10.1111/cbdd.14196] [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: 10/17/2022] [Revised: 11/23/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
One of the leading causes of death worldwide is cancer, which poses substantial risks to both society and an individual's life. Cancer therapy is still challenging, despite developments in the field and continued research into cancer prevention. The search for novel anticancer active agents with a broader cytotoxicity range is therefore continuously ongoing. The benzene ring gets fused to a pyridine ring at two carbon atoms close to one another to form the double ring structure of the heterocyclic aromatic nitrogen molecule known as quinoline (1-azanaphthalene). Quinoline derivatives contain a wide range of pharmacological activities, including antitubercular, antifungal, antibacterial, and antimalarial properties. Quinoline derivatives have also been shown to have anticancer properties. There are many quinoline derivatives widely available as anticancer drugs that act via a variety of mechanisms on various molecular targets, such as inhibition of topoisomerase, inhibition of tyrosine kinases, inhibition of heat shock protein 90 (Hsp90), inhibition of histone deacetylases (HDACs), inhibition of cell cycle arrest and apoptosis, and inhibition of tubulin polymerization.
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Affiliation(s)
- Vikas Pradhan
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute), Greater Noida
| | - Salahuddin
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute), Greater Noida
| | - Rajnish Kumar
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute), Greater Noida
| | - Avijit Mazumder
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute), Greater Noida
| | | | - Mohammad Shahar Yar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, New Delhi
| | - Mohamed Jawed Ahsan
- Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy, Jaipur, Rajasthan, India
| | - Zabih Ullah
- Department of Pharmaceutical Sciences, College of Dentistry and Pharmacy, Buraydah Colleges, Al-Qassim, Saudi Arabia
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Ma B, Liu Y, Pan W, Li Z, Ren C, Hu C, Luo P. Integrative Application of Transcriptomics and Metabolomics Provides Insights into Unsynchronized Growth in Sea Cucumber ( Stichopus monotuberculatus). Int J Mol Sci 2022; 23:15478. [PMID: 36555118 PMCID: PMC9779819 DOI: 10.3390/ijms232415478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/28/2022] [Accepted: 12/03/2022] [Indexed: 12/12/2022] Open
Abstract
Ever-increasing consumer demand for sea cucumbers mainly leads to huge damage to wild sea cucumber resources, including Stichopus monotuberculatus, which in turn exerts negative impacts on marine environments due to the lack of ecological functions performed by sea cucumbers. Aquaculture of sea cucumbers is an effective way to meet consumer demand and restore their resources. Unsynchronous growth is a prominent problem in the aquaculture of sea cucumbers which has concealed unelucidated molecular mechanisms until now. In this study, we carried out an integrative analysis of transcriptomics and metabolomics on fast-growing (SMF) and slow-growing (SMS) groups of S. monotuberculatus cultured in the same environmental conditions. The results revealed that a total of 2054 significantly differentially expressed genes (DEGs) were identified, which are mainly involved in fat digestion and absorption, histidine metabolism, arachidonic acid metabolism, and glutathione metabolism. 368 differential metabolites (DMs) were screened out between the SMF group and the SMS group; these metabolites are mainly involved in glycerophospholipid metabolism, purine metabolism, biosynthesis of unsaturated fatty acids, pyrimidine metabolism, arachidonic acid metabolism, and other metabolic pathways. The integrative analysis of transcriptomics and metabolomics of S. monotuberculatus suggested that the SMF group had a higher capacity for lipid metabolism and protein synthesis, and had a more frequent occurrence of apoptosis events, which are likely to be related to coping with environmental stresses. The results of this study provide potential values for the aquaculture of sea cucumbers which may promote their resource enhancement.
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Affiliation(s)
- Bo Ma
- CAS Key Laboratory of Tropical Marine Bioresources and Ecology (LMB), Guangdong Provincial Key Laboratory of Applied Marine Biology (LAMB), South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510000, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou 510000, China
| | - Yang Liu
- CAS Key Laboratory of Tropical Marine Bioresources and Ecology (LMB), Guangdong Provincial Key Laboratory of Applied Marine Biology (LAMB), South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510000, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou 510000, China
| | - Wenjie Pan
- CAS Key Laboratory of Tropical Marine Bioresources and Ecology (LMB), Guangdong Provincial Key Laboratory of Applied Marine Biology (LAMB), South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510000, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou 510000, China
| | - Zhuobo Li
- CAS Key Laboratory of Tropical Marine Bioresources and Ecology (LMB), Guangdong Provincial Key Laboratory of Applied Marine Biology (LAMB), South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510000, China
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou 510000, China
| | - Chunhua Ren
- CAS Key Laboratory of Tropical Marine Bioresources and Ecology (LMB), Guangdong Provincial Key Laboratory of Applied Marine Biology (LAMB), South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510000, China
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou 510000, China
| | - Chaoqun Hu
- CAS Key Laboratory of Tropical Marine Bioresources and Ecology (LMB), Guangdong Provincial Key Laboratory of Applied Marine Biology (LAMB), South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510000, China
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou 510000, China
| | - Peng Luo
- CAS Key Laboratory of Tropical Marine Bioresources and Ecology (LMB), Guangdong Provincial Key Laboratory of Applied Marine Biology (LAMB), South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510000, China
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou 510000, China
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Apoptosis induction in human prostate cancer cells related to the fatty acid metabolism by wogonin-mediated regulation of the AKT-SREBP1-FASN signaling network. Food Chem Toxicol 2022; 169:113450. [DOI: 10.1016/j.fct.2022.113450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 09/04/2022] [Accepted: 09/28/2022] [Indexed: 11/21/2022]
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Dialysis as a Novel Adjuvant Treatment for Malignant Cancers. Cancers (Basel) 2022; 14:cancers14205054. [PMID: 36291840 PMCID: PMC9600214 DOI: 10.3390/cancers14205054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/05/2022] [Accepted: 10/12/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary There is a clear need for new cancer therapies as many cancers have a very short long-term survival rate. For most advanced cancers, therapy resistance limits the benefit of any single-agent chemotherapy, radiotherapy, or immunotherapy. Cancer cells show a greater dependence on glucose and glutamine as fuel than healthy cells do. In this article, we propose using 4- to 8-h dialysis treatments to change the blood composition, i.e., lowering glucose and glutamine levels, and elevating ketone levels—thereby disrupting major metabolic pathways important for cancer cell survival. The dialysis’ impact on cancer cells include not only metabolic effects, but also redox balance, immunological, and epigenetic effects. These pleiotropic effects could potentially enhance the effectiveness of traditional cancer treatments, such as radiotherapies, chemotherapies, and immunotherapies—resulting in improved outcomes and longer survival rates for cancer patients. Abstract Cancer metabolism is characterized by an increased utilization of fermentable fuels, such as glucose and glutamine, which support cancer cell survival by increasing resistance to both oxidative stress and the inherent immune system in humans. Dialysis has the power to shift the patient from a state dependent on glucose and glutamine to a ketogenic condition (KC) combined with low glutamine levels—thereby forcing ATP production through the Krebs cycle. By the force of dialysis, the cancer cells will be deprived of their preferred fermentable fuels, disrupting major metabolic pathways important for the ability of the cancer cells to survive. Dialysis has the potential to reduce glucose levels below physiological levels, concurrently increase blood ketone body levels and reduce glutamine levels, which may further reinforce the impact of the KC. Importantly, ketones also induce epigenetic changes imposed by histone deacetylates (HDAC) activity (Class I and Class IIa) known to play an important role in cancer metabolism. Thus, dialysis could be an impactful and safe adjuvant treatment, sensitizing cancer cells to traditional cancer treatments (TCTs), potentially making these significantly more efficient.
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Oberle R, Kührer K, Österreicher T, Weber F, Steinbauer S, Udonta F, Wroblewski M, Ben-Batalla I, Hassl I, Körbelin J, Unseld M, Jauhiainen M, Plochberger B, Röhrl C, Hengstschläger M, Loges S, Stangl H. The HDL particle composition determines its antitumor activity in pancreatic cancer. Life Sci Alliance 2022; 5:e202101317. [PMID: 35577388 PMCID: PMC9112193 DOI: 10.26508/lsa.202101317] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 05/02/2022] [Accepted: 05/03/2022] [Indexed: 12/03/2022] Open
Abstract
Despite enormous efforts to improve therapeutic options, pancreatic cancer remains a fatal disease and is expected to become the second leading cause of cancer-related deaths in the next decade. Previous research identified lipid metabolic pathways to be highly enriched in pancreatic ductal adenocarcinoma (PDAC) cells. Thereby, cholesterol uptake and synthesis promotes growth advantage to and chemotherapy resistance for PDAC tumor cells. Here, we demonstrate that high-density lipoprotein (HDL)-mediated efficient cholesterol removal from cancer cells results in PDAC cell growth reduction and induction of apoptosis in vitro. This effect is driven by an HDL particle composition-dependent interaction with SR-B1 and ABCA1 on cancer cells. AAV-mediated overexpression of APOA1 and rHDL injections decreased PDAC tumor development in vivo. Interestingly, plasma samples from pancreatic-cancer patients displayed a significantly reduced APOA1-to-SAA1 ratio and a reduced cholesterol efflux capacity compared with healthy donors. We conclude that efficient, HDL-mediated cholesterol depletion represents an interesting strategy to interfere with the aggressive growth characteristics of PDAC.
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Affiliation(s)
- Raimund Oberle
- Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria
| | - Kristina Kührer
- Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria
| | - Tamina Österreicher
- Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria
| | - Florian Weber
- School of Medical Engineering and Applied Social Sciences, University of Applied Sciences Upper Austria, Linz, Austria
| | - Stefanie Steinbauer
- Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Wels, Austria
| | - Florian Udonta
- Department of Oncology, Hematology and Bone Marrow Transplantation, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mark Wroblewski
- Department of Oncology, Hematology and Bone Marrow Transplantation, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Isabel Ben-Batalla
- Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ingrid Hassl
- Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria
| | - Jakob Körbelin
- ENDomics Lab, Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Matthias Unseld
- Department of Medicine I, Division of Palliative Medicine, Medical University of Vienna, Vienna, Austria
| | - Matti Jauhiainen
- Minerva Foundation Institute for Medical Research and Finnish Institute for Health and Welfare, Genomics and Biobank Unit, Biomedicum 2U, Helsinki, Finland
| | - Birgit Plochberger
- School of Medical Engineering and Applied Social Sciences, University of Applied Sciences Upper Austria, Linz, Austria
| | - Clemens Röhrl
- Center of Excellence Food Technology and Nutrition, University of Applied Sciences Upper Austria, Wels, Austria
| | - Markus Hengstschläger
- Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria
| | - Sonja Loges
- Department of Personalized Oncology, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Herbert Stangl
- Center for Pathobiochemistry and Genetics, Medical University of Vienna, Vienna, Austria
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(20S) Ginsenoside Rh2-Activated, Distinct Apoptosis Pathways in Highly and Poorly Differentiated Human Esophageal Cancer Cells. Molecules 2022; 27:molecules27175602. [PMID: 36080369 PMCID: PMC9457866 DOI: 10.3390/molecules27175602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/28/2022] Open
Abstract
Ginsenoside Rh2 (G-Rh2), a rare ginsenoside isolated from red ginseng, has considerable anti-cancer activity and induces apoptosis in a variety of cancer cells, but its activity in esophageal cancer cells is unclear. In this study, we examined the cytotoxic activity of (20S) G-Rh2 in highly differentiated esophageal squamous ECA109 cells and poorly differentiated esophageal squamous TE-13 cells. (20S) G-Rh2 exerted intense cytotoxicity in ECA109 and TE-13 cells with an IC50 of 2.9 and 3.7 μg/mL, respectively. After treatment with G-Rh2, Bcl-2, and Bcl-xL, the two main anti-apoptosis Bcl-2 family proteins upregulated, and Bax and Bak, the two key pro-apoptosis proteins translocated to mitochondria in both cell lines. At the same time, cytochrome c and Smac released from mitochondria, followed by caspase-9 activation, indicating that a mitochondria-mediated intrinsic apoptosis pathway was activated in both cell lines upon treatment with (20S) G-Rh2. It is noteworthy that (20S) G-Rh2 upregulated the transcription and protein expression of two death receptors, Fas and DR5, and subsequently activated Caspase-8 in the TE-13 cells but not in the ECA109 cells. Taken together, we demonstrated the potent anti-esophageal cancer cell activity of (20S) G-Rh2 and showed its working mechanism in two differentiated esophageal cancer cells, which can provide important evidence for developing an effective strategy for anti-esophageal cancer treatment.
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Fan N, Fu H, Feng X, Chen Y, Wang J, Wu Y, Bian Y, Li Y. Long non-coding RNAs play an important regulatory role in tumorigenesis and tumor progression through aerobic glycolysis. Front Mol Biosci 2022; 9:941653. [PMID: 36072431 PMCID: PMC9441491 DOI: 10.3389/fmolb.2022.941653] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Compared to normal cells, cancer cells generate ATP mainly through aerobic glycolysis, which promotes tumorigenesis and tumor progression. Long non-coding RNAs (LncRNAs) are a class of transcripts longer than 200 nucleotides with little or without evident protein-encoding function. LncRNAs are involved in the ten hallmarks of cancer, interestingly, they are also closely associated with aerobic glycolysis. However, the mechanism of this process is non-transparent to date. Demonstrating the mechanism of lncRNAs regulating tumorigenesis and tumor progression through aerobic glycolysis is particularly critical for cancer therapy, and may provide novel therapeutic targets or strategies in cancer treatment. In this review, we discuss the role of lncRNAs and aerobic glycolysis in tumorigenesis and tumor progression, and further explore their interaction, in hope to provide a novel therapeutic target for cancer treatment.
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Affiliation(s)
- Ni Fan
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hui Fu
- College of Integrated Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xuchen Feng
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yatong Chen
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jingyu Wang
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuqi Wu
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuhong Bian
- College of Integrated Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- *Correspondence: Yuhong Bian, ; Yingpeng Li,
| | - Yingpeng Li
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- *Correspondence: Yuhong Bian, ; Yingpeng Li,
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Long noncoding RNA CERS6-AS1 modulates glucose metabolism and tumor progression in hepatocellular carcinoma by promoting the MDM2/p53 signaling pathway. Cell Death Dis 2022; 8:348. [PMID: 35927226 PMCID: PMC9352870 DOI: 10.1038/s41420-022-01150-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 07/23/2022] [Accepted: 07/26/2022] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most serious malignant cancers and has a high fatality rate. However, clinical strategies for the effective treatment of HCC remain lacking. Long non-coding RNAs (lncRNAs) with aberrant expression have been closely correlated with the occurrence and development of HCC. Here we investigated the underlying mechanism of the lncRNA CERS6-AS1 in HCC progression. The expression and prognosis of CERS6-AS1 in HCC patients was explored using The Cancer Genome Atlas. PCR analysis was utilized to measure the expression of CERS6-AS1 in tissues and cell lines. Transwell, wound healing, proliferation and glycolysis assays were conducted to evaluate the function of CERS6-AS1 on HCC cell functions. Bioinformation methods and luciferase assays were used to screen and verify potential target miRNAs and genes. A subcutaneous tumorigenesis model was constructed in nude mice to assess the effect of CERS6-AS1 on tumorigenesis in vivo. CERS6-AS1 was highly expressed in HCC tissues and cell lines. Upregulated CERS6-AS1 expression was remarkably correlated with poor prognosis of HCC patients. High CERS6-AS1 expression facilitated cell growth, invasion and glycolysis of HCC cells. Bioinformatics analyses combining with PCR analysis identified miR-30b-3p as the potential target of CERS6-AS1, and MDM2 mRNA was verified as the target of miR-30b-3p. The expression of miR-30b-3p was negatively correlated with CERS6-AS1, whereas MDM2 was positively associated with CERS6-AS1. Mechanistic studies showed that CERS6-AS1 may sponge miR-30b-3p to elevate MDM2, thus promoting the MDM2-mediated ubiquitin-dependent degradation of the p53 tumor suppressor. MDM2 overexpression or miR-30b-3p inhibitors blocked the inhibitory effect of CERS6-AS1 knockdown on proliferation, migration and glycolysis. CERS6-AS1 depletion reduced tumor formation in the in vivo mouse model. The CERS6-AS1/miR-30b-3p/MDM2/p53 signaling axis may play key roles in regulating HCC progression. CERS6-AS1 may exert as a novel biomarker or therapeutic target for HCC.
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Kholodenko IV, Gisina AM, Manukyan GV, Majouga AG, Svirshchevskaya EV, Kholodenko RV, Yarygin KN. Resistance of Human Liver Mesenchymal Stem Cells to FAS-Induced Cell Death. Curr Issues Mol Biol 2022; 44:3428-3443. [PMID: 36005132 PMCID: PMC9406952 DOI: 10.3390/cimb44080236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/26/2022] [Accepted: 07/28/2022] [Indexed: 11/05/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have a pronounced therapeutic potential in various pathological conditions. Though therapeutic effects of MSC transplantation have been studied for a long time, the underlying mechanisms are still not clear. It has been shown that transplanted MSCs are rapidly eliminated, presumably by apoptosis. As the mechanisms of MSC apoptosis are not fully understood, in the present work we analyzed MSC sensitivity to Fas-induced apoptosis using MSCs isolated from the biopsies of liver fibrosis patients (L-MSCs). The level of cell death was analyzed by flow cytometry in the propidium iodide test. The luminescent ATP assay was used to measure cellular ATP levels; and the mitochondrial membrane potential was assessed using the potential-dependent dye JC-1. We found that human L-MSCs were resistant to Fas-induced cell death over a wide range of FasL and anti-Fas mAb concentrations. At the same time, intrinsic death signal inducers CoCl2 and staurosporine caused apoptosis of L-MSCs in a dose-dependent manner. Despite the absence of Fas-induced cell death treatment of L-MSCs with low concentrations of FasL or anti-Fas mAb resulted in a cellular ATP level decrease, while high concentrations of the inducers caused a decline of the mitochondrial membrane potential. Pre-incubation of L-MSCs with the pro-inflammatory cytokine TNF-α did not promote L-MSC cell death. Our data indicate that human L-MSCs have increased resistance to receptor-mediated cell death even under inflammatory conditions.
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Affiliation(s)
- Irina V. Kholodenko
- Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia; (A.M.G.); (K.N.Y.)
- Correspondence: ; Tel.: +7-(905)7765062; Fax: +7-(499)2450857
| | - Alisa M. Gisina
- Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia; (A.M.G.); (K.N.Y.)
| | - Garik V. Manukyan
- Petrovsky Russian Research Center of Surgery, 119991 Moscow, Russia;
| | - Alexander G. Majouga
- Faculty of Chemical and Pharmaceutical Technologies and Biomedical Products, Mendeleev University of Chemical Technology of Russia, 125047 Moscow, Russia;
| | - Elena V. Svirshchevskaya
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (E.V.S.); (R.V.K.)
| | - Roman V. Kholodenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; (E.V.S.); (R.V.K.)
| | - Konstantin N. Yarygin
- Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia; (A.M.G.); (K.N.Y.)
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Khodaei A, Jahanmard F, Madaah Hosseini H, Bagheri R, Dabbagh A, Weinans H, Amin Yavari S. Controlled temperature-mediated curcumin release from magneto-thermal nanocarriers to kill bone tumors. Bioact Mater 2022; 11:107-117. [PMID: 34938916 PMCID: PMC8665343 DOI: 10.1016/j.bioactmat.2021.09.028] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 08/11/2021] [Accepted: 09/23/2021] [Indexed: 01/10/2023] Open
Abstract
Systemic chemotherapy has lost its position to treat cancer over the past years mainly due to drug resistance, side effects, and limited survival ratio. Among a plethora of local drug delivery systems to solve this issue, the combinatorial strategy of chemo-hyperthermia has recently received attention. Herein we developed a magneto-thermal nanocarrier consisted of superparamagnetic iron oxide nanoparticles (SPIONs) coated by a blend formulation of a three-block copolymer Pluronic F127 and F68 on the oleic acid (OA) in which Curcumin as a natural and chemical anti-cancer agent was loaded. The subsequent nanocarrier SPION@OA-F127/F68-Cur was designed with a controlled gelation temperature of the shell, which could consequently control the release of curcumin. The release was systematically studied as a function of temperature and pH, via response surface methodology (RSM). The bone tumor killing efficacy of the released curcumin from the carrier in combination with the hyperthermia was studied on MG-63 osteosarcoma cells through Alamar blue assay, live-dead staining and apoptosis caspase 3/7 activation kit. It was found that the shrinkage of the F127/F68 layer stimulated by elevated temperature in an alternative magnetic field caused the curcumin release. Although the maximum release concentration and cell death took place at 45 °C, treatment at 41 °C was chosen as the optimum condition due to considerable cell apoptosis and lower side effects of mild hyperthermia. The cell metabolic activity results confirmed the synergistic effects of curcumin and hyperthermia in killing MG-63 osteosarcoma cells.
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Affiliation(s)
- A. Khodaei
- Institute for Nanoscience and Nanotechnology, Sharif University of Technology, Tehran, Iran
- Department of Orthopedics, University Medical Center Utrecht, Utrecht, the Netherlands
| | - F. Jahanmard
- Department of Orthopedics, University Medical Center Utrecht, Utrecht, the Netherlands
| | - H.R. Madaah Hosseini
- Department of Materials Science and Engineering, Sharif University of Technology, Tehran, Iran
| | - R. Bagheri
- Department of Materials Science and Engineering, Sharif University of Technology, Tehran, Iran
| | - A. Dabbagh
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| | - H. Weinans
- Department of Orthopedics, University Medical Center Utrecht, Utrecht, the Netherlands
| | - S. Amin Yavari
- Department of Orthopedics, University Medical Center Utrecht, Utrecht, the Netherlands
- Regenerative Medicine Utrecht, Utrecht University, Utrecht, the Netherlands
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Kaya Çakir H, Eroglu O. In vitro anti-proliferative effect of capecitabine (Xeloda) combined with mocetinostat (MGCD0103) in 4T1 breast cancer cell line by immunoblotting. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2022; 24:1515-1522. [PMID: 35317122 PMCID: PMC8917851 DOI: 10.22038/ijbms.2021.58393.12971] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 10/06/2021] [Indexed: 11/06/2022]
Abstract
Objectives Mouse breast cancer cell line 4T1 can accurately mimic the response to immune receptors and targeting therapeutic agents. Combined therapy has emerged as an important strategy with reduced side effects and maximum therapeutic effect. Mocetinostat (MGCD0103) is one of the members of Class I Histone Deacetylase Inhibitors (HDACi) and its mechanism of action has not been defined, yet. Capecitabine (Xeloda) is an antimetabolite and currently is widely utilized to treat a wide range of solid tumors. The aim of this study was to investigate the effects of the capecitabine, mocetinostat and their combined application on the 4T1 cell line. Materials and Methods The effects of combined administration of mocetinostat and capecitabine on 4T1 cells were investigated by cell viability and migration assays, apoptosis analysis, and Western blotting technique. Results The concentrations of drugs that give a half-maximal response (IC50) were detected for capecitabine (1700 µM), mocetinostat (3,125 µM), and 50 µM Capecitabine+1,5 µM Mocetinostat for 48 hr. In capecitabine+mocetinostat combine group, we observed that cell migration decreased, DNA fragmentation increased compared to the control group. capecitabine + mocetinostat group induced apoptosis by decreasing Bcl-2, PI3K, Akt, c-myc protein levels, while increasing Bax, Caspase-3, PTEN, cleaved-PARP, Caspase-7, Caspase-9, p53, cleaved-Cas-9 protein levels in 4T1 cells. Conclusion Capecitabine and mocetinostat played a toxic role through inducing apoptosis on 4T1 cancer cells in a time- and concentration-dependent manner. These results showed that combined therapy with low concentrations were detected to be more effective than that with high-concentration alone drug treatment.
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Affiliation(s)
- Hacer Kaya Çakir
- Department of Molecular Biology and Genetics, Faculty of Science and Letters, Bilecik Seyh Edebali University, Bilecik, Turkey.,Biotechnology Research and Application Center, Bilecik Seyh Edebali University, Bilecik, Turkey
| | - Onur Eroglu
- Department of Molecular Biology and Genetics, Faculty of Science and Letters, Bilecik Seyh Edebali University, Bilecik, Turkey.,Biotechnology Research and Application Center, Bilecik Seyh Edebali University, Bilecik, Turkey
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Allen CNS, Arjona SP, Santerre M, Sawaya BE. Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis. Viruses 2022; 14:602. [PMID: 35337009 PMCID: PMC8955778 DOI: 10.3390/v14030602] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 02/07/2023] Open
Abstract
Metabolic reprogramming is a hallmark of cancer and has proven to be critical in viral infections. Metabolic reprogramming provides the cell with energy and biomass for large-scale biosynthesis. Based on studies of the cellular changes that contribute to metabolic reprogramming, seven main hallmarks can be identified: (1) increased glycolysis and lactic acid, (2) increased glutaminolysis, (3) increased pentose phosphate pathway, (4) mitochondrial changes, (5) increased lipid metabolism, (6) changes in amino acid metabolism, and (7) changes in other biosynthetic and bioenergetic pathways. Viruses depend on metabolic reprogramming to increase biomass to fuel viral genome replication and production of new virions. Viruses take advantage of the non-metabolic effects of metabolic reprogramming, creating an anti-apoptotic environment and evading the immune system. Other non-metabolic effects can negatively affect cellular function. Understanding the role metabolic reprogramming plays in viral pathogenesis may provide better therapeutic targets for antivirals.
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Affiliation(s)
- Charles N. S. Allen
- Molecular Studies of Neurodegenerative Diseases Lab, FELS Cancer Institute for Personalized Medicine Institute, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (S.P.A.); (M.S.)
| | - Sterling P. Arjona
- Molecular Studies of Neurodegenerative Diseases Lab, FELS Cancer Institute for Personalized Medicine Institute, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (S.P.A.); (M.S.)
| | - Maryline Santerre
- Molecular Studies of Neurodegenerative Diseases Lab, FELS Cancer Institute for Personalized Medicine Institute, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (S.P.A.); (M.S.)
| | - Bassel E. Sawaya
- Molecular Studies of Neurodegenerative Diseases Lab, FELS Cancer Institute for Personalized Medicine Institute, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; (C.N.S.A.); (S.P.A.); (M.S.)
- Departments of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Department of Cancer and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
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Lin S, Sheng Q, Ma X, Li S, Xu P, Dai C, Wang M, Kang H, Dai Z. Marsdenia tenacissima Extract Induces Autophagy and Apoptosis of Hepatocellular Cells via MIF/mToR Signaling. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:7354700. [PMID: 35280512 PMCID: PMC8916871 DOI: 10.1155/2022/7354700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 12/23/2021] [Accepted: 01/07/2022] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) seriously endangers humans. In traditional Chinese medicine, Marsdenia tenacissima (MTE) has anti-inflammatory, antiasthmatic, antihypertensive, and anticancer effects. This study reveals the antiproliferative effect of MTE on the HCC cells in vitro and provides a theoretical basis for the development and clinical application of anti-HCC agents. Methods. MHCC-97H and HepG2 cells were cultured in vitro and exposed to various concentrations and durations of MTE, and an MTT assay was used to detect the effects of MTE on cell proliferation. Transmission electron microscopy revealed the morphological changes in the two cell lines after MTE stimulation. The MTE effects on the apoptosis and cell cycle distribution of the cell lines were detected by flow cytometry. Western blotting and qRT-PCR were used to detect target gene expression at the protein and mRNA levels, respectively. Results. MTE reduced the viability of the MHCC-97H and HepG2 cells in a dose- and time-dependent manners (P < 0.05). Autophagic vesicles and apoptotic bodies were found in the MHCC-97H and HepG2 cells after MTE incubation, and the Annexin V-PI assay showed that the apoptotic rates of the cell lines increased with increasing MTE concentration (P < 0.05). Autophagy inducer rapamycin promoted the MTE-induced apoptotic rates of the cell lines, whereas autophagy inhibitor chloroquine inhibited the apoptotic rates. More cells in the S phase were found in the two cell lines after MTE treatment (P < 0.05). After MTE incubation, MIF, CD47, and beclin-1 protein levels significantly increased. Furthermore, in the MTE group, Akt, mTOR, and caspase3 expressions decreased; however, LC 3 expression increased, which was significantly different from the control group (P < 0.05). Conclusions. MTE inhibited proliferation and induced autophagy, apoptosis, and S phase cell cycle arrest in the MHCC-97H and HepG2 cells. These effects might be related to the activation of MIF and mTOR signaling inhibition.
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Affiliation(s)
- Shuai Lin
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Qianwen Sheng
- Department of Oncology, Xi'an International Medical Center Hospital, Xi'an, China
| | - Xiaobin Ma
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Shanli Li
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Peng Xu
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Cong Dai
- Department of Thyroid Breast Surgery, Xi'an International Medical Center Hospital, Xi'an, China
| | - Meng Wang
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Huafeng Kang
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Zhijun Dai
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
- Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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Qi M, Xu D, Wang S, Li B, Peng S, Li Q, Zhang H, Fan R, Chen H, Kong MG. In Vivo Metabolic Analysis of the Anticancer Effects of Plasma-Activated Saline in Three Tumor Animal Models. Biomedicines 2022; 10:biomedicines10030528. [PMID: 35327329 PMCID: PMC8945198 DOI: 10.3390/biomedicines10030528] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/12/2022] [Accepted: 02/20/2022] [Indexed: 02/04/2023] Open
Abstract
In recent years, the emerging technology of cold atmospheric pressure plasma (CAP) has grown rapidly along with the many medical applications of cold plasma (e.g., cancer, skin disease, tissue repair, etc.). Plasma-activated liquids (e.g., culture media, water, or normal saline, previously exposed to plasma) are being studied as cancer treatments, and due to their advantages, many researchers prefer plasma-activated liquids as an alternative to CAP in the treatment of cancer. In this study, we showed that plasma-activated-saline (PAS) treatment significantly inhibited tumor growth, as compared with saline, in melanoma, and a low-pH environment had little effect on tumor growth in vivo. In addition, based on an ultra-high-performance liquid tandem chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) analysis of tumor cell metabolism, the glycerophospholipid metabolic pathway was the most susceptible metabolic pathway to PAS treatment in melanoma in vitro and in vivo. Furthermore, PAS also inhibited cell proliferation in vivo in oral tongue squamous-cell cancer and non-small-cell lung cancer. There were few toxic side effects in the three animal models, and the treatment was deemed safe to use. In the future, plasma-activated liquids may serve as a potential therapeutic approach in the treatment of cancer.
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Affiliation(s)
- Miao Qi
- State Key Laboratory of Electrical Insulation and Power Equipment, Centre for Plasma Biomedicine, Xi’an Jiaotong University, Xi’an 710049, China; (M.Q.); (S.P.); (Q.L.); (H.Z.); (R.F.)
- The School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (S.W.); (B.L.)
| | - Dehui Xu
- State Key Laboratory of Electrical Insulation and Power Equipment, Centre for Plasma Biomedicine, Xi’an Jiaotong University, Xi’an 710049, China; (M.Q.); (S.P.); (Q.L.); (H.Z.); (R.F.)
- Correspondence: (D.X.); (M.G.K.)
| | - Shuai Wang
- The School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (S.W.); (B.L.)
| | - Bing Li
- The School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, China; (S.W.); (B.L.)
| | - Sansan Peng
- State Key Laboratory of Electrical Insulation and Power Equipment, Centre for Plasma Biomedicine, Xi’an Jiaotong University, Xi’an 710049, China; (M.Q.); (S.P.); (Q.L.); (H.Z.); (R.F.)
| | - Qiaosong Li
- State Key Laboratory of Electrical Insulation and Power Equipment, Centre for Plasma Biomedicine, Xi’an Jiaotong University, Xi’an 710049, China; (M.Q.); (S.P.); (Q.L.); (H.Z.); (R.F.)
| | - Hao Zhang
- State Key Laboratory of Electrical Insulation and Power Equipment, Centre for Plasma Biomedicine, Xi’an Jiaotong University, Xi’an 710049, China; (M.Q.); (S.P.); (Q.L.); (H.Z.); (R.F.)
| | - Runze Fan
- State Key Laboratory of Electrical Insulation and Power Equipment, Centre for Plasma Biomedicine, Xi’an Jiaotong University, Xi’an 710049, China; (M.Q.); (S.P.); (Q.L.); (H.Z.); (R.F.)
| | - Hailan Chen
- Frank Reidy Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, USA;
| | - Michael G. Kong
- Frank Reidy Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508, USA;
- Department of Electrical and Computer Engineering, Old Dominion University, Norfolk, VA 23529, USA
- Correspondence: (D.X.); (M.G.K.)
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Extra-Virgin Olive Oil and Its Minor Compounds Influence Apoptosis in Experimental Mammary Tumors and Human Breast Cancer Cell Lines. Cancers (Basel) 2022; 14:cancers14040905. [PMID: 35205652 PMCID: PMC8870719 DOI: 10.3390/cancers14040905] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 02/07/2022] [Accepted: 02/08/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Breast cancer is a disease influenced by dietetic factors, such as the type and amount of lipids in a diet. In this work, we aimed to elucidate the different effects of two high-fat diets on the histopathological and molecular characteristics of mammary tumors in an experimental model. Animals fed with a diet high in extra-virgin olive oil (EVOO), compared to those fed with a diet high in seed oil, developed tumors with less aggressiveness and proliferation. Tumor molecular analyses of several cell death pathways also suggested an effect of EVOO in this process. In vitro experiments indicated the role of EVOO minor compounds on the effects of this oil. Obtaining insights into the influence and the mechanisms of action of dietary compounds are necessary to understand the relevance that dietetic habits from childhood may have on health and the risk of disease. Abstract Breast cancer is the most common malignancy among women worldwide. Modifiable factors such as nutrition have a role in its etiology. In experimental tumors, we have observed the differential influence of high-fat diets in metabolic pathways, suggesting a different balance in proliferation/apoptosis. In this work, we analyzed the effects of a diet high in n-6 polyunsaturated fatty acids (PUFA) and a diet high in extra-virgin olive oil (EVOO) on the histopathological features and different cell death pathways in the dimethylbenz(a)anthracene-induced breast cancer model. The diet high in n-6 PUFA had a stimulating effect on the morphological aggressiveness of tumors and their proliferation, while no significant differences were found in groups fed the EVOO-enriched diet in comparison to a low-fat control group. The high-EVOO diet induced modifications in proteins involved in several cell death pathways. In vitro analysis in different human breast cancer cell lines showed an effect of EVOO minor compounds (especially hydroxytyrosol), but not of fatty acids, decreasing viability while increasing apoptosis. The results suggest an effect of dietary lipids on tumor molecular contexts that result in the modulation of different pathways, highlighting the importance of apoptosis in the interplay of survival processes and how dietary habits may have an impact on breast cancer risk.
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Doll MA, Ray AR, Salazar-González RA, Shah PP, Vega AA, Sears SM, Krueger AM, Hong KU, Beverly LJ, Hein DW. Deletion of arylamine N-acetyltransferase 1 in MDA-MB-231 human breast cancer cells reduces primary and secondary tumor growth in vivo with no significant effects on metastasis. Mol Carcinog 2022; 61:481-493. [PMID: 35133049 PMCID: PMC9018511 DOI: 10.1002/mc.23392] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 12/20/2021] [Accepted: 01/03/2022] [Indexed: 12/13/2022]
Abstract
Arylamine N-acetyltransferase 1 (NAT1) is frequently upregulated in breast cancer. Previous studies showed that inhibition or depletion of NAT1 in breast cancer cells diminishes anchorage-independent growth in culture, suggesting that NAT1 contributes to breast cancer growth and metastasis. To further investigate the contribution of NAT1 to growth and cell invasive/migratory behavior, we subjected parental and NAT1 knockout (KO) breast cancer cell lines (MDA-MB-231, MCF-7, and ZR-75-1) to multiple assays. The rate of cell growth in suspension was not consistently decreased in NAT1 KO cells across the cell lines tested. Similarly, cell migration and invasion assays failed to produce reproducible differences between the parental and NAT1 KO cells. To overcome the limitations of in vitro assays, we tested parental and NAT1 KO cells in vivo in a xenograft model by injecting cells into the flank of immunocompromised mice. NAT1 KO MDA-MB-231 cells produced primary tumors smaller than those formed by parental cells, which was contributed by an increased rate of apoptosis in KO cells. The frequency of lung metastasis, however, was not altered in NAT1 KO cells. When the primary tumors of the parental and NAT1 KO cells were allowed to grow to a pre-determined size or delivered directly via tail vein, the number and size of metastatic foci in the lung did not differ between the parental and NAT1 KO cells. In conclusion, NAT1 contributes to primary and secondary tumor growth in vivo in MDA-MB-231 breast cancer cells but does not appear to affect its metastatic potential.
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Affiliation(s)
- Mark A Doll
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA
| | - Andrew R Ray
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA
| | - Raúl A Salazar-González
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA
| | - Parag P Shah
- Department of Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Alexis A Vega
- Department of Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Sophia M Sears
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA
| | - Austin M Krueger
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA
| | - Kyung U Hong
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA.,Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
| | - Levi J Beverly
- Department of Medicine, University of Louisville, Louisville, Kentucky, USA.,Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
| | - David W Hein
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA.,Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
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