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1
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Zhang S, Wang YS, Li Y, To KI, Zhang ET, Jin YH. Annexin A2 binds the 3'-UTR of H2AX mRNA and regulates histone-H2AX-derived hypoxia-inducible factor 1-alpha activation. Cell Signal 2025; 132:111781. [PMID: 40164417 DOI: 10.1016/j.cellsig.2025.111781] [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: 12/28/2024] [Revised: 03/21/2025] [Accepted: 03/28/2025] [Indexed: 04/02/2025]
Abstract
Annexin A2 (Anxa2), a multifunctional protein with RNA-binding capabilities, is frequently overexpressed in various tumors, and its expression is highly correlated with malignant progression. In this study, we demonstrate for the first time that Anxa2 was co-expressed with glycolytic genes, suggesting its potential role as a regulator of glycolysis. RNA-protein interaction assay revealed that Anxa2 interacted with 3'-UTR of H2AX mRNA and protected it from miRNA-mediated degradation. Up-regulated Histone-H2AX enhances the expression of glycolytic genes including GLUT1, HK2, PGK1, ENO1, PKM2, GAPDH and LDHA via stabilizing hypoxia-inducible factor 1-alpha (HIF1α), thereby accelerating lactic acid production and secretion. (20S) G-Rh2, a natural compound targeting Anxa2, significantly interfered the Anxa2-H2AX mRNA interaction, and inhibited subsequent glycolysis progression. We propose that Anxa2 acts as a novel regulator in glycolysis via enhancing H2AX expression, and (20S) G-Rh2 may exert its anti-cancer activity by targeting Anxa2-H2AX-HIF1α-glycolysis axis in human hepatoma HepG2 cells.
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Affiliation(s)
- Shiyin Zhang
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Yu-Shi Wang
- Department of Criminal Science and Technology, Jilin Police College, Changchun 130117, China
| | - Yang Li
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Kwang-Il To
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - En-Ting Zhang
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China
| | - Ying-Hua Jin
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, China.
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2
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Hsu TW, Wang WY, Chen HA, Wang TH, Su CM, Liao PH, Chen A, Tsai KY, Kokotos G, Kuo CC, Chiu CF, Su YH. FOXO3a/miR-4259-driven LDHA expression as a key mechanism of gemcitabine sensitivity in pancreatic ductal adenocarcinoma. Cancer Metab 2025; 13:7. [PMID: 39930542 PMCID: PMC11809001 DOI: 10.1186/s40170-025-00377-3] [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: 12/04/2024] [Accepted: 01/31/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Lactate dehydrogenase A (LDHA) can regulate tumorigenesis and cancer progression. Nevertheless, whether the regulation of LDHA is involved in the development of gemcitabine resistance in PDAC has not yet been fully elucidated. Increasing studies have shown that cancer acquired drug resistance led to treatment failure is highly attributed to the cancer stem cell (CSC) properties. Therefore, we aim to demonstrate the functions and regulatory mechanisms of LDHA on cancer stem cell (CSC) properties and gemcitabine resistance in PDAC. METHODS We investigate the metabolite profiles by liquid chromatography-mass spectrometry between gemcitabine-resistant PDAC and parental PDAC cells. Additionally, gain-of-function and loss-of-function experiments were conducted to examine the roles of LDHA on CSC properties and gemcitabine resistance in the gemcitabine-resistant PDAC and parental PDAC cells. To investigate regulators involved in LDHA-mediated gemcitabine resistance and CSC of pancreatic cancer cells, we further used a combination of the miRNA microarray results and software predictions and confirmed that miR-4259 is a direct target of LDHA by luciferase assay. Furthermore, we constructed serial miR-4259 promoter reporters and searched for response elements using the TESS 2.0/TFSEARCH software to find the transcription factor binding site in the promoter region of miR-4259. RESULTS We observed that elevated LDHA expression significantly correlates with recurrent pancreatic cancer patients following gemcitabine treatment and with CSC properties. We further identify that FOXO3a-induced miR-4259 directly targets the 3'untranslated region of LDHA and reduced LDHA expression, leading to decreased gemcitabine resistance and a reduction in the CSC phenotypes of pancreatic cancer. CONCLUSION Our results demonstrated that LDHA plays a critical role in cancer stemness and gemcitabine resistance of pancreatic cancer, and indicate that targeting the FOXO3a/miR-4259/LDHA pathway might serve as a new treatment for pancreatic cancer patients with a poor response to gemcitabine chemotherapy.
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Affiliation(s)
- Tung-Wei Hsu
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Wan-Yu Wang
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Hsin-An Chen
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Department of Surgery, Division of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
- TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Tzu-Hsuan Wang
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Chih-Ming Su
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Department of Surgery, Division of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Po-Hsiang Liao
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Alvin Chen
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Kuei-Yen Tsai
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Department of Surgery, Division of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - George Kokotos
- Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens, Greece
| | - Cheng-Chin Kuo
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan
- Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan, Taiwan
| | - Ching-Feng Chiu
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Yen-Hao Su
- Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
- Department of Surgery, Division of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
- TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, Taiwan.
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
- Metabolic and Weight Management Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
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3
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Zhong L, Zheng J, Wang Z, Lin L, Cong Q, Qiao L. Metabolomics and proteomics reveal the inhibitory effect of Lactobacillus crispatus on cervical cancer. Talanta 2025; 281:126839. [PMID: 39265423 DOI: 10.1016/j.talanta.2024.126839] [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: 07/15/2024] [Revised: 09/04/2024] [Accepted: 09/07/2024] [Indexed: 09/14/2024]
Abstract
Cervical cancer remains a significant global health issue due to its high morbidity and mortality rates. Recently, Lactobacillus crispatus has been recognized for its crucial role in maintaining cervical health. While some studies have explored the use of L. crispatus to mitigate cervical cancer, the underlying mechanisms remain largely unknown. In this study, we employed non-targeted proteomics and metabolomics to investigate how L. crispatus affects the growth of cervical cancer cells (SiHa) and normal cervical cells (Ect1/E6E7). Our findings indicated that the inhibitory effect of L. crispatus on SiHa cells was associated with various biological processes, notably the ferroptosis pathway. Specifically, L. crispatus was found to regulate the expression of proteins such as HMOX1, SLC39A14, VDAC2, ACSL4, and LPCAT3 by SiHa cells, which are closely related to ferroptosis. Additionally, it activated the tricarboxylic acid (TCA) cycle in SiHa cells, leading to increased levels of reactive oxygen species (ROS) and lipid peroxides (LPO). These results revealed the therapeutic potential of L. crispatus in targeting the ferroptosis pathway for cervical cancer treatment, opening new avenues for research and therapy in cervical cancer.
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Affiliation(s)
- Lingyan Zhong
- Department of Chemistry, Zhongshan Hospital, and Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200000, China
| | - Jianxujie Zheng
- Department of Chemistry, Zhongshan Hospital, and Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200000, China
| | - Zengyu Wang
- Department of Chemistry, Zhongshan Hospital, and Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200000, China
| | - Ling Lin
- Department of Chemistry, Zhongshan Hospital, and Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200000, China.
| | - Qing Cong
- Department of Chemistry, Zhongshan Hospital, and Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200000, China.
| | - Liang Qiao
- Department of Chemistry, Zhongshan Hospital, and Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200000, China.
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Ozgencil F, Gunindi HB, Eren G. Dual-targeted NAMPT inhibitors as a progressive strategy for cancer therapy. Bioorg Chem 2024; 149:107509. [PMID: 38824699 DOI: 10.1016/j.bioorg.2024.107509] [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: 03/09/2024] [Revised: 04/29/2024] [Accepted: 05/28/2024] [Indexed: 06/04/2024]
Abstract
In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in the nicotinamide adenine dinucleotide (NAD+) synthesis pathway catalyzing the condensation of nicotinamide (NAM) with 5-phosphoribosyl-1-pyrophosphate (PRPP) to produce nicotinamide mononucleotide (NMN). Given the pivotal role of NAD+ in a range of cellular functions, including DNA synthesis, redox reactions, cytokine generation, metabolism, and aging, NAMPT has become a promising target for many diseases, notably cancer. Therefore, various NAMPT inhibitors have been reported and classified as first and second-generation based on their chemical structures and design strategies, dual-targeted being one. However, most NAMPT inhibitors suffer from several limitations, such as dose-dependent toxicity and poor pharmacokinetic properties. Consequently, there is no clinically approved NAMPT inhibitor. Hence, research on discovering more effective and less toxic dual-targeted NAMPT inhibitors with desirable pharmacokinetic properties has drawn attention recently. This review summarizes the previously reported dual-targeted NAMPT inhibitors, focusing on their design strategies and advantages over the single-targeted therapies.
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Affiliation(s)
- Fikriye Ozgencil
- SIRTeam Group, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Türkiye
| | - Habibe Beyza Gunindi
- SIRTeam Group, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Türkiye
| | - Gokcen Eren
- SIRTeam Group, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Türkiye.
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Wang L, Zhang RK, Sang P, Xie YX, Zhang Y, Zhou ZH, Wang KK, Zhou FM, Ji XB, Liu WJ, Qiu JG, Jiang BH. HK2 and LDHA upregulation mediate hexavalent chromium-induced carcinogenesis, cancer development and prognosis through miR-218 inhibition. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 279:116500. [PMID: 38795416 DOI: 10.1016/j.ecoenv.2024.116500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 05/16/2024] [Accepted: 05/22/2024] [Indexed: 05/28/2024]
Abstract
Hexavalent chromium [Cr(VI)] is one of the most common environmental contaminants due to its tremendous industrial applications, but its effects and mechanism remain to be investigated. Our previous studies showed that Cr(VI) exposure caused malignant transformation and tumorigenesis. This study showed that glycolytic proteins HK2 and LDHA levels were statistically significant changed in blood samples of Cr(VI)-exposed workers and in Cr-T cells compared to the control subjects and parental cells. HK2 and LDHA knockdown inhibited cell proliferation and angiogenesis, and higher HK2 and LDHA expression levels are associated with advanced stages and poor prognosis of lung cancer. We found that miR-218 levels were significantly decreased and miR-218 directly targeted HK2 and LDHA for inhibiting their expression. Overexpression of miR-218 inhibited glucose consumption and lactate production in Cr-T cells. Further study found that miR-218 inhibited tumor growth and angiogenesis by decreasing HK2 and LDHA expression in vivo. MiR-218 levels were negatively correlated with HK2 and LDHA expression levels and cancer development in human lung and other cancers. These results demonstrated that miR-218/HK2/LDHA pathway is vital for regulating Cr(VI)-induced carcinogenesis and human cancer development.
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Affiliation(s)
- Lin Wang
- Academy of Medical Science, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China
| | - Rui-Ke Zhang
- Academy of Medical Science, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China
| | - Peng Sang
- Academy of Medical Science, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China
| | - Yun-Xia Xie
- Academy of Medical Science, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China
| | - Ye Zhang
- The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Zhi-Hao Zhou
- Academy of Medical Science, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China
| | - Kun-Kun Wang
- Academy of Medical Science, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China
| | - Feng-Mei Zhou
- Academy of Medical Science, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China
| | - Xiang-Bo Ji
- Academy of Medical Science, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China
| | - Wen-Jing Liu
- The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Jian-Ge Qiu
- Academy of Medical Science, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China.
| | - Bing-Hua Jiang
- Academy of Medical Science, Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou University, Zhengzhou 450000, China.
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6
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Bosso M, Haddad D, Al Madhoun A, Al-Mulla F. Targeting the Metabolic Paradigms in Cancer and Diabetes. Biomedicines 2024; 12:211. [PMID: 38255314 PMCID: PMC10813379 DOI: 10.3390/biomedicines12010211] [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: 11/29/2023] [Revised: 01/09/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
Dysregulated metabolic dynamics are evident in both cancer and diabetes, with metabolic alterations representing a facet of the myriad changes observed in these conditions. This review delves into the commonalities in metabolism between cancer and type 2 diabetes (T2D), focusing specifically on the contrasting roles of oxidative phosphorylation (OXPHOS) and glycolysis as primary energy-generating pathways within cells. Building on earlier research, we explore how a shift towards one pathway over the other serves as a foundational aspect in the development of cancer and T2D. Unlike previous reviews, we posit that this shift may occur in seemingly opposing yet complementary directions, akin to the Yin and Yang concept. These metabolic fluctuations reveal an intricate network of underlying defective signaling pathways, orchestrating the pathogenesis and progression of each disease. The Warburg phenomenon, characterized by the prevalence of aerobic glycolysis over minimal to no OXPHOS, emerges as the predominant metabolic phenotype in cancer. Conversely, in T2D, the prevailing metabolic paradigm has traditionally been perceived in terms of discrete irregularities rather than an OXPHOS-to-glycolysis shift. Throughout T2D pathogenesis, OXPHOS remains consistently heightened due to chronic hyperglycemia or hyperinsulinemia. In advanced insulin resistance and T2D, the metabolic landscape becomes more complex, featuring differential tissue-specific alterations that affect OXPHOS. Recent findings suggest that addressing the metabolic imbalance in both cancer and diabetes could offer an effective treatment strategy. Numerous pharmaceutical and nutritional modalities exhibiting therapeutic effects in both conditions ultimately modulate the OXPHOS-glycolysis axis. Noteworthy nutritional adjuncts, such as alpha-lipoic acid, flavonoids, and glutamine, demonstrate the ability to reprogram metabolism, exerting anti-tumor and anti-diabetic effects. Similarly, pharmacological agents like metformin exhibit therapeutic efficacy in both T2D and cancer. This review discusses the molecular mechanisms underlying these metabolic shifts and explores promising therapeutic strategies aimed at reversing the metabolic imbalance in both disease scenarios.
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Affiliation(s)
- Mira Bosso
- Department of Pathology, Faculty of Medicine, Health Science Center, Kuwait University, Safat 13110, Kuwait
| | - Dania Haddad
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (D.H.); (A.A.M.)
| | - Ashraf Al Madhoun
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (D.H.); (A.A.M.)
- Department of Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Fahd Al-Mulla
- Department of Pathology, Faculty of Medicine, Health Science Center, Kuwait University, Safat 13110, Kuwait
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (D.H.); (A.A.M.)
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7
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Zhang Y, Zheng F, Wang F, Liu X, Xiang C, Fu S, Shen K, Liu G. The Expression of Two Distinct Sets of Glycolytic Enzymes Reveals Differential Effects of Glycolytic Reprogramming on Pancreatic Ductal Tumorigenesis in Mice. Biomedicines 2023; 11:2962. [PMID: 38001963 PMCID: PMC10669313 DOI: 10.3390/biomedicines11112962] [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: 09/04/2023] [Revised: 10/17/2023] [Accepted: 10/31/2023] [Indexed: 11/26/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with enhanced aerobic glycolysis through elevated glucose uptake and the upregulated expression of genes encoding rate-limiting glycolytic enzymes. However, the direct impact of altered glycolytic pathways on pancreatic tumor progression has not been thoroughly investigated. Here, we utilized two strains of BAC transgenic mice with pancreatic expression of two distinct sets of glycolytic genes each arranged in a polycistronic fashion (PFKFB3-HK2-GLUT1 and LDHA-PDK1, respectively) to investigate the role of altered glycolysis on the development of pancreatic ductal tumor development in the Pdx1-Cre; LSL-KrasG12D mice. The overexpression of the two sets of glycolytic genes exhibited no significant effects on tumor development in the 4-5-month-old mice (the PanIN2 lesions stage). In the 9-10-month-old mice, the overexpression of PFKFB3-HK2-GLUT1 significantly accelerated PanIN3 progression, exhibiting elevated levels of ductal cell marker CK19 and tumor fibrosis. Surprisingly, the overexpression of LDHA-PDK1 significantly attenuated the progression of PanIN3 in the 9-10-month-old mice with significantly downregulated levels of CK19 and fibrosis. Therefore, distinct set of glycolytic enzymes that are involved in different glycolytic routes exhibited contrasting effects on pancreatic ductal tumor development depending on the tumor stages, providing novel insights into the complexity of the glycolytic pathway in the perspective of PDAC development and therapy.
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Affiliation(s)
| | | | | | | | | | | | | | - Geng Liu
- State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animals for Disease Study, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, 12 Xuefu Road, Pukou High-Tech District, Nanjing 210061, China; (Y.Z.); (F.Z.); (F.W.); (X.L.); (C.X.); (S.F.); (K.S.)
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8
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Cimmino TP, Pagano E, Stornaiuolo M, Esposito G, Ammendola R, Cattaneo F. Formyl-peptide receptor 2 signalling triggers aerobic metabolism of glucose through Nox2-dependent modulation of pyruvate dehydrogenase activity. Open Biol 2023; 13:230336. [PMID: 37875162 PMCID: PMC10597678 DOI: 10.1098/rsob.230336] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 09/20/2023] [Indexed: 10/26/2023] Open
Abstract
The human formyl-peptide receptor 2 (FPR2) is activated by an array of ligands. By phospho-proteomic analysis we proved that FPR2 stimulation induces redox-regulated phosphorylation of many proteins involved in cellular metabolic processes. In this study, we investigated metabolic pathways activated in FPR2-stimulated CaLu-6 cells. The results showed an increased concentration of metabolites involved in glucose metabolism, and an enhanced uptake of glucose mediated by GLUT4, the insulin-regulated member of GLUT family. Accordingly, we observed that FPR2 transactivated IGF-IRβ/IRβ through a molecular mechanism that requires Nox2 activity. Since cancer cells support their metabolism via glycolysis, we analysed glucose oxidation and proved that FPR2 signalling promoted kinase activity of the bifunctional enzyme PFKFB2 through FGFR1/FRS2- and Akt-dependent phosphorylation. Furthermore, FPR2 stimulation induced IGF-IRβ/IRβ-, PI3K/Akt- and Nox-dependent inhibition of pyruvate dehydrogenase activity, thus preventing the entry of pyruvate in the tricarboxylic acid cycle. Consequently, we observed an enhanced FGFR-dependent lactate dehydrogenase (LDH) activity and lactate production in FPR2-stimulated cells. As LDH expression is transcriptionally regulated by c-Myc and HIF-1, we demonstrated that FPR2 signalling promoted c-Myc phosphorylation and Nox-dependent HIF-1α stabilization. These results strongly indicate that FPR2-dependent signalling can be explored as a new therapeutic target in treatment of human cancers.
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Affiliation(s)
- Tiziana Pecchillo Cimmino
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
| | - Ester Pagano
- Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
| | - Mariano Stornaiuolo
- Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
| | - Gabriella Esposito
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
| | - Rosario Ammendola
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
| | - Fabio Cattaneo
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy
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9
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Takata N, Miska JM, Morgan MA, Patel P, Billingham LK, Joshi N, Schipma MJ, Dumar ZJ, Joshi NR, Misharin AV, Embry RB, Fiore L, Gao P, Diebold LP, McElroy GS, Shilatifard A, Chandel NS, Oliver G. Lactate-dependent transcriptional regulation controls mammalian eye morphogenesis. Nat Commun 2023; 14:4129. [PMID: 37452018 PMCID: PMC10349100 DOI: 10.1038/s41467-023-39672-2] [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: 06/20/2022] [Accepted: 06/26/2023] [Indexed: 07/18/2023] Open
Abstract
Mammalian retinal metabolism favors aerobic glycolysis. However, the role of glycolytic metabolism in retinal morphogenesis remains unknown. We report that aerobic glycolysis is necessary for the early stages of retinal development. Taking advantage of an unbiased approach that combines the use of eye organoids and single-cell RNA sequencing, we identify specific glucose transporters and glycolytic genes in retinal progenitors. Next, we determine that the optic vesicle territory of mouse embryos displays elevated levels of glycolytic activity. At the functional level, we show that removal of Glucose transporter 1 and Lactate dehydrogenase A gene activity from developing retinal progenitors arrests eye morphogenesis. Surprisingly, we uncover that lactate-mediated upregulation of key eye-field transcription factors is controlled by the epigenetic modification of histone H3 acetylation through histone deacetylase activity. Our results identify an unexpected bioenergetic independent role of lactate as a signaling molecule necessary for mammalian eye morphogenesis.
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Affiliation(s)
- Nozomu Takata
- Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, 303 E. Superior Street, Chicago, IL, 60611, USA
| | - Jason M Miska
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Marc A Morgan
- Simpson Querrey Institute for Epigenetics and Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
| | - Priyam Patel
- Center for Genetic Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Leah K Billingham
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Neha Joshi
- Center for Genetic Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Matthew J Schipma
- Center for Genetic Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Zachary J Dumar
- Simpson Querrey Institute for Epigenetics and Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Nikita R Joshi
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Alexander V Misharin
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Ryan B Embry
- Center for Genetic Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Luciano Fiore
- Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Laboratory of Nanomedicine, National Atomic Energy Commission (CNEA), Av. General Paz 1499, B1650KNA, San Martín, Buenos Aires, Argentina
| | - Peng Gao
- Robert H. Lurie Cancer Center Metabolomics Core, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Lauren P Diebold
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Gregory S McElroy
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA
- Department of Ophthalmology, Duke University School of Medicine, Durham, NC, 27710, USA
| | - Ali Shilatifard
- Simpson Querrey Institute for Epigenetics and Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Navdeep S Chandel
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Guillermo Oliver
- Center for Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
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10
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Black R, Barentsz J, Howell D, Bostwick DG, Strum SB. Optimized 18F-FDG PET-CT Method to Improve Accuracy of Diagnosis of Metastatic Cancer. Diagnostics (Basel) 2023; 13:diagnostics13091580. [PMID: 37174971 PMCID: PMC10178450 DOI: 10.3390/diagnostics13091580] [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: 03/13/2023] [Revised: 03/28/2023] [Accepted: 04/12/2023] [Indexed: 05/15/2023] Open
Abstract
The diagnosis of cancer by FDG PET-CT is often inaccurate owing to subjectivity of interpretation. We compared the accuracy of a novel normalized (standardized) method of interpretation with conventional non-normalized SUV. Patients (n = 393) with various malignancies were studied with FDG PET/CT to determine the presence or absence of cancer. Target lesions were assessed by two methods: (1) conventional SUVmax (conSUVmax) and (2) a novel method that combined multiple factors to optimize SUV (optSUVmax), including the patient's normal liver SUVmax, a liver constant (k) derived from a review of the literature, and use of site-specific thresholds for malignancy. The two methods were compared to pathology findings in 154 patients being evaluated for mediastinal and/or hilar lymph node (MHLNs) metastases, 143 evaluated for extra-thoracic lymph node (ETLNs) metastases, and 96 evaluated for liver metastases. OptSUVmax was superior to conSUVmax for all patient groups. For MHLNs, sensitivity was 83.8% vs. 80.7% and specificity 88.7% vs. 9.6%, respectively; for ETLNs, sensitivity was 92.1% vs. 77.8% and specificity 80.1% vs. 27.6%, respectively; and for lesions in the liver parenchyma, sensitivity was 96.1% vs. 82.3% and specificity 88.8% vs. 23.0%, respectively. Optimized SUVmax increased diagnostic accuracy of FDG PET-CT for cancer when compared with conventional SUVmax interpretation.
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Affiliation(s)
| | - Jelle Barentsz
- Department of Radiology, Andros Clinics, Meester E.N. van Kleffensstraat 5, 6842 CV Arnhem, The Netherlands
| | - David Howell
- Department of Radiation Oncology, Ohio Health Cancer Center, 75 Hospital Drive, Athens, OH 45701, USA
| | - David G Bostwick
- Rampart Health, 601 Biotech Drive, North Chesterfield, VA 23235, USA
| | - Stephen B Strum
- Community Practice of Hematology, Oncology and Internal Medicine, Focus on Prostate Cancer and Prostate Diseases, Medford, OR 97504, USA
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11
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Rastogi S, Aldosary S, Saeedan AS, Ansari MN, Singh M, Kaithwas G. NF-κB mediated regulation of tumor cell proliferation in hypoxic microenvironment. Front Pharmacol 2023; 14:1108915. [PMID: 36891273 PMCID: PMC9986608 DOI: 10.3389/fphar.2023.1108915] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 02/01/2023] [Indexed: 02/22/2023] Open
Abstract
Hypoxia is caused by a cancer-promoting milieu characterized by persistent inflammation. NF-κB and HIF-1α are critical participants in this transition. Tumor development and maintenance are aided by NF-κB, while cellular proliferation and adaptability to angiogenic signals are aided by HIF-1α. Prolyl hydroxylase-2 (PHD-2) has been hypothesized to be the key oxygen-dependent regulator of HIF-1α and NF-transcriptional B's activity. Without low oxygen levels, HIF-1α is degraded by the proteasome in a process dependent on oxygen and 2-oxoglutarate. As opposed to the normal NF-κB activation route, where NF-κB is deactivated by PHD-2-mediated hydroxylation of IKK, this method actually activates NF-κB. HIF-1α is protected from degradation by proteasomes in hypoxic cells, where it then activates transcription factors involved in cellular metastasis and angiogenesis. The Pasteur phenomenon causes lactate to build up inside the hypoxic cells. As part of a process known as lactate shuttle, MCT-1 and MCT-4 cells help deliver lactate from the blood to neighboring, non-hypoxic tumour cells. Non-hypoxic tumour cells use lactate, which is converted to pyruvate, as fuel for oxidative phosphorylation. OXOPHOS cancer cells are characterized by a metabolic switch from glucose-facilitated oxidative phosphorylation to lactate-facilitated oxidative phosphorylation. Although PHD-2 was found in OXOPHOS cells. There is no clear explanation for the presence of NF-kappa B activity. The accumulation of the competitive inhibitor of 2-oxo-glutarate, pyruvate, in non-hypoxic tumour cells is well established. So, we conclude that PHD-2 is inactive in non-hypoxic tumour cells due to pyruvate-mediated competitive suppression of 2-oxo-glutarate. This results in canonical activation of NF-κB. In non-hypoxic tumour cells, 2-oxoglutarate serves as a limiting factor, rendering PHD-2 inactive. However, FIH prevents HIF-1α from engaging in its transcriptional actions. Using the existing scientific literature, we conclude in this study that NF-κB is the major regulator of tumour cell growth and proliferation via pyruvate-mediated competitive inhibition of PHD-2.
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Affiliation(s)
- Shubham Rastogi
- Department of Pharmaceutical Sciences, School of Biosciences and Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India
| | - Sara Aldosary
- Department of Pharmaceutical Sciences, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Abdulaziz S Saeedan
- Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Mohd Nazam Ansari
- Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Manjari Singh
- Department of Pharmaceutical Sciences, Assam Central University, Silchar, India
| | - Gaurav Kaithwas
- Department of Pharmaceutical Sciences, School of Biosciences and Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India
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12
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Qiu S, Wang Y, Rao H, Que Q, Wu Y, Zhu R, Feng X, Chi J, Lai W, Sun Y, Xiao Q, Shi H, Xiang Y. Tumor microenvironment-associated lactate metabolism regulates the prognosis and precise checkpoint immunotherapy outcomes of patients with lung adenocarcinoma. Eur J Med Res 2022; 27:256. [PMID: 36411477 PMCID: PMC9677690 DOI: 10.1186/s40001-022-00895-6] [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: 08/18/2022] [Accepted: 11/09/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Despite the wide clinical application of checkpoint inhibitor immunotherapy in lung adenocarcinoma, its limited benefit to patients remains puzzling to researchers. One of the mechanisms of immunotherapy resistance may be the dysregulation of lactate metabolism in the immunosuppressive tumor microenvironment (TME), which can inhibit dendritic cell maturation and prevent T-cell invasion into tumors. However, the key genes related to lactate metabolism and their influence on the immunotherapeutic effects in lung adenocarcinoma have not yet been investigated in depth. METHODS In this study, we first surveyed the dysregulated expression of genes related to lactate metabolism in lung adenocarcinoma and then characterized their biological functions. Using machine learning methods, we constructed a lactate-associated gene signature in The Cancer Genome Atlas cohort and validated its effectiveness in predicting the prognosis and immunotherapy outcomes of patients in the Gene Expression Omnibus cohorts. RESULTS A 7-gene signature based on the metabolomics related to lactate metabolism was found to be associated with multiple important clinical features of cancer and was an independent prognostic factor. CONCLUSIONS These results suggest that rather than being simply a metabolic byproduct of glycolysis, lactate in the TME can affect immunotherapy outcomes. Therefore, the mechanism underlying this effect of lactate is worthy of further study.
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Affiliation(s)
- Song Qiu
- grid.440714.20000 0004 1797 9454Department of Oncology, The First Affiliated Hospital, Gannan Medical University, No 23, Qingnian Road, Ganzhou, China
| | - Ying Wang
- grid.440714.20000 0004 1797 9454Department of Oncology, The First Affiliated Hospital, Gannan Medical University, No 23, Qingnian Road, Ganzhou, China
| | - Hui Rao
- grid.440714.20000 0004 1797 9454Department of Oncology, The First Affiliated Hospital, Gannan Medical University, No 23, Qingnian Road, Ganzhou, China
| | - Qiuyang Que
- grid.440714.20000 0004 1797 9454Department of Oncology, The First Affiliated Hospital, Gannan Medical University, No 23, Qingnian Road, Ganzhou, China
| | - Yanyang Wu
- grid.440714.20000 0004 1797 9454Department of Oncology, The First Affiliated Hospital, Gannan Medical University, No 23, Qingnian Road, Ganzhou, China
| | - Rui Zhu
- grid.440714.20000 0004 1797 9454Department of Oncology, The First Affiliated Hospital, Gannan Medical University, No 23, Qingnian Road, Ganzhou, China
| | - Xiaofei Feng
- grid.440714.20000 0004 1797 9454Department of Oncology, The First Affiliated Hospital, Gannan Medical University, No 23, Qingnian Road, Ganzhou, China
| | - Jun Chi
- grid.440714.20000 0004 1797 9454Department of Oncology, The First Affiliated Hospital, Gannan Medical University, No 23, Qingnian Road, Ganzhou, China
| | - Weiling Lai
- grid.440714.20000 0004 1797 9454Department of Oncology, The First Affiliated Hospital, Gannan Medical University, No 23, Qingnian Road, Ganzhou, China
| | - Yihang Sun
- grid.284723.80000 0000 8877 7471School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Qi Xiao
- Jiangkou Town Central Health Center, Ganxian District, Ganzhou, China
| | - Huaqiu Shi
- grid.440714.20000 0004 1797 9454Department of Oncology, The First Affiliated Hospital, Gannan Medical University, No 23, Qingnian Road, Ganzhou, China
| | - Yi Xiang
- grid.440714.20000 0004 1797 9454Department of Oncology, The First Affiliated Hospital, Gannan Medical University, No 23, Qingnian Road, Ganzhou, China
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13
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Govoni M, Rossi V, Di Stefano G, Manerba M. Lactate Upregulates the Expression of DNA Repair Genes, Causing Intrinsic Resistance of Cancer Cells to Cisplatin. Pathol Oncol Res 2022; 27:1609951. [PMID: 34987311 PMCID: PMC8720744 DOI: 10.3389/pore.2021.1609951] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 11/30/2021] [Indexed: 12/28/2022]
Abstract
Intrinsic or acquired drug resistance is one of the major problems compromising the success of antineoplastic treatments. Several evidences correlated some therapeutic failures with changes in cell metabolic asset and in line with these findings, hindering the glycolytic metabolism of cancer cells via lactate dehydrogenase (LDH) inhibition was found to overcome the resistance to chemotherapeutic agents. Lactate, the product of LDH reaction, was shown to be involved in epigenetic regulation of gene expression. The experiments described in this paper were aimed at highlighting a possible direct effect of lactate in modifying the response of cancer cells to a chemotherapeutic treatment. To discriminate between the effects potentially caused by glycolytic metabolism from those directly referable to lactate, we selected cancer cell lines able to grow in glucose deprived conditions and evaluated the impact of lactate on the cellular response to cisplatin-induced DNA damage. In lactate-exposed cells we observed a reduced efficacy of cisplatin, which was associated with reduced signatures of DNA damage, enhanced DNA recombination competence and increased expression of a panel of genes involved in DNA repair. The identified genes take part in mismatch and nucleotide excision repair pathways, which were found to contribute in restoring the cisplatin-induced DNA damage. The obtained results suggest that this metabolite could play a role in reducing the efficacy of antineoplastic treatments.
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Affiliation(s)
- Marzia Govoni
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Valentina Rossi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Giuseppina Di Stefano
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Marcella Manerba
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
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14
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The Anticancer Ruthenium Compound BOLD-100 Targets Glycolysis and Generates a Metabolic Vulnerability towards Glucose Deprivation. Pharmaceutics 2022; 14:pharmaceutics14020238. [PMID: 35213972 PMCID: PMC8875291 DOI: 10.3390/pharmaceutics14020238] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 12/13/2022] Open
Abstract
Cellular energy metabolism is reprogrammed in cancer to fuel proliferation. In oncological therapy, treatment resistance remains an obstacle and is frequently linked to metabolic perturbations. Identifying metabolic changes as vulnerabilities opens up novel approaches for the prevention or targeting of acquired therapy resistance. Insights into metabolic alterations underlying ruthenium-based chemotherapy resistance remain widely elusive. In this study, colon cancer HCT116 and pancreatic cancer Capan-1 cells were selected for resistance against the clinically evaluated ruthenium complex sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (BOLD-100). Gene expression profiling identified transcriptional deregulation of carbohydrate metabolism as a response to BOLD-100 and in resistance against the drug. Mechanistically, acquired BOLD-100 resistance is linked to elevated glucose uptake and an increased lysosomal compartment, based on a defect in downstream autophagy execution. Congruently, metabolomics suggested stronger glycolytic activity, in agreement with the distinct hypersensitivity of BOLD-100-resistant cells to 2-deoxy-d-glucose (2-DG). In resistant cells, 2-DG induced stronger metabolic perturbations associated with ER stress induction and cytoplasmic lysosome deregulation. The combination with 2-DG enhanced BOLD-100 activity against HCT116 and Capan-1 cells and reverted acquired BOLD-100 resistance by synergistic cell death induction and autophagy disturbance. This newly identified enhanced glycolytic activity as a metabolic vulnerability in BOLD-100 resistance suggests the targeting of glycolysis as a promising strategy to support BOLD-100 anticancer activity.
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15
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Béland-Millar A, Messier C. Voluntary Behavior and Training Conditions Modulate in vivo Extracellular Glucose and Lactate in the Mouse Primary Motor Cortex. Front Neurosci 2022; 15:732242. [PMID: 35058739 PMCID: PMC8764159 DOI: 10.3389/fnins.2021.732242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 11/10/2021] [Indexed: 11/13/2022] Open
Abstract
Learning or performing new behaviors requires significant neuronal signaling and is metabolically demanding. The metabolic cost of performing a behavior is mitigated by exposure and practice which result in diminished signaling and metabolic requirements. We examined the impact of novel and habituated wheel running, as well as effortful behaviors on the modulation of extracellular glucose and lactate using biosensors inserted in the primary motor cortex of mice. We found that motor behaviors produce increases in extracellular lactate and decreases in extracellular glucose in the primary motor cortex. These effects were modulated by experience, novelty and intensity of the behavior. The increase in extracellular lactate appears to be strongly associated with novelty of a behavior as well as the difficulty of performing a behavior. Our observations are consistent with the view that a main function of aerobic glycolysis is not to fuel the current neuronal activity but to sustain new bio-infrastructure as learning changes neural networks, chiefly through the shuttling of glucose derived carbons into the pentose phosphate pathway for the biosynthesis of nucleotides.
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Affiliation(s)
| | - Claude Messier
- School of Psychology, University of Ottawa, Ottawa, ON, Canada
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16
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Rezaei-Tazangi F, Roghani-Shahraki H, Khorsand Ghaffari M, Abolhasani Zadeh F, Boostan A, ArefNezhad R, Motedayyen H. The Therapeutic Potential of Common Herbal and Nano-Based Herbal Formulations against Ovarian Cancer: New Insight into the Current Evidence. Pharmaceuticals (Basel) 2021; 14:1315. [PMID: 34959716 PMCID: PMC8705681 DOI: 10.3390/ph14121315] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/28/2021] [Accepted: 11/30/2021] [Indexed: 12/19/2022] Open
Abstract
Ovarian cancer (OCa) is characterized as one of the common reasons for cancer-associated death in women globally. This gynecological disorder is chiefly named the "silent killer" due to lacking an association between disease manifestations in the early stages and OCa. Because of the disease recurrence and resistance to common therapies, discovering an effective therapeutic way against the disease is a challenge. According to documents, some popular herbal formulations, such as curcumin, quercetin, and resveratrol, can serve as an anti-cancer agent through different mechanisms. However, these herbal products may be accompanied by some pharmacological limitations, such as poor bioavailability, instability, and weak water solubility. On the contrary, using nano-based material, e.g., nanoparticles (NPs), micelles, liposomes, can significantly solve these limitations. Therefore, in the present study, we will summarize the anti-cancer aspects of these herbal and-nano-based herbal formulations with a focus on their mechanisms against OCa.
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Affiliation(s)
- Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa 7345149573, Iran;
| | | | - Mahdi Khorsand Ghaffari
- Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz 1433671348, Iran;
| | - Firoozeh Abolhasani Zadeh
- Department of Surgery, Faculty of Medicine, Kerman University of Medical Sciences, Kerman 7616913555, Iran;
| | - Aynaz Boostan
- Department of Obstetrics & Gynecology, Saveh Chamran Hospital, Saveh 3919676651, Iran;
| | - Reza ArefNezhad
- Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz 1433671348, Iran
| | - Hossein Motedayyen
- Autoimmune Diseases Research Center, Kashan University of Medical Sciences, Kashan 8715973474, Iran
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17
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Fleminger G, Dayan A. The moonlighting activities of dihydrolipoamide dehydrogenase: Biotechnological and biomedical applications. J Mol Recognit 2021; 34:e2924. [PMID: 34164859 DOI: 10.1002/jmr.2924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 06/13/2021] [Indexed: 12/13/2022]
Abstract
Dihydrolipoamide dehydrogenase (DLDH) is a homodimeric flavin-dependent enzyme that catalyzes the NAD+ -dependent oxidation of dihydrolipoamide. The enzyme is part of several multi-enzyme complexes such as the Pyruvate Dehydrogenase system that transforms pyruvate into acetyl-co-A. Concomitantly with its redox activity, DLDH produces Reactive Oxygen Species (ROS), which are involved in cellular apoptotic processes. DLDH possesses several moonlighting functions. One of these is the capacity to adhere to metal-oxides surfaces. This was first exemplified by the presence of an exocellular form of the enzyme on the cell-wall surface of Rhodococcus ruber. This capability was evolutionarily conserved and identified in the human, mitochondrial, DLDH. The enzyme was modified with Arg-Gly-Asp (RGD) groups, which enabled its interaction with integrin-rich cancer cells followed by "integrin-assisted-endocytosis." This allowed harnessing the enzyme for cancer therapy. Combining the TiO2 -binding property with DLDH's ROS-production, enabled us to develop several medical applications including improving oesseointegration of TiO2 -based implants and photodynamic treatment for melanoma. The TiO2 -binding sites of both the bacterial and human DLDH's were identified on the proteins' molecules at regions that overlap with the binding site of E3-binding protein (E3BP). This protein is essential in forming the multiunit structure of PDC. Another moonlighting activity of DLDH, which is described in this Review, is its DNA-binding capacity that may affect DNA chelation and shredding leading to apoptotic processes in living cells. The typical ROS-generation by DLDH, which occurs in association with its enzymatic activity and its implications in cancer and apoptotic cell death are also discussed.
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Affiliation(s)
- Gideon Fleminger
- The Shmunis School of Biomedicine and Cancer Research, The George Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel
| | - Avraham Dayan
- The Shmunis School of Biomedicine and Cancer Research, The George Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel
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18
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Ding N, Xu S, Zheng S, Ye Q, Xu L, Ling S, Xie S, Chen W, Zhang Z, Xue M, Lin Z, Xu X, Wang L. "Sweet tooth"-oriented SN38 prodrug delivery nanoplatform for targeted gastric cancer therapy. J Mater Chem B 2021; 9:2816-2830. [PMID: 33690741 DOI: 10.1039/d0tb02787a] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Most cancer cells employ overexpression of glucose transports (GLUTs) to satisfy glucose demand ("Sweet Tooth") for increased aerobic glycolysis rates. GLUT1, one of the most widely expressed GLUTs in numerous cancers, was identified as a prognosis-related biomarker of gastric cancer via tissue array analysis. Herein, a "Sweet Tooth"-oriented SN38 prodrug delivery nanoplatform (Glu-SNP) was developed for targeted gastric cancer therapy. For this purpose, a SN38-derived prodrug (PLA-SN38) was synthesized by tethering 7-ethyl-10-hydroxycamptothecin (SN38) to biocompatible polylactic acid (PLA) with the appropriate degree of polymerization (n = 44). The PLA-SN38 conjugate was further assembled with glycosylated amphiphilic lipid to obtain glucosamine-decorated nanoparticles (Glu-SNP). Glu-SNP exhibited potent antitumor efficiency both in vitro and in vivo through enhanced cancer cell-specific targeting associated with the overexpression of GLUT1, which provides a promising approach for gastric cancer therapy.
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Affiliation(s)
- Ning Ding
- Department of Gastroenterology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310020, China.
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19
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Shriwas P, Roberts D, Li Y, Wang L, Qian Y, Bergmeier S, Hines J, Adhicary S, Nielsen C, Chen X. A small-molecule pan-class I glucose transporter inhibitor reduces cancer cell proliferation in vitro and tumor growth in vivo by targeting glucose-based metabolism. Cancer Metab 2021; 9:14. [PMID: 33771231 PMCID: PMC8004435 DOI: 10.1186/s40170-021-00248-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 03/03/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Cancer cells drastically increase the uptake of glucose and glucose metabolism by overexpressing class I glucose transporters (GLUT1-4) to meet their energy and biomass synthesis needs and are very sensitive and vulnerable to glucose deprivation. Although targeting glucose uptake via GLUTs has been an attractive anticancer strategy, the relative anticancer efficacy of multi-GLUT targeting or single GLUT targeting is unclear. Here, we report DRB18, a synthetic small molecule, is a potent anticancer compound whose pan-class I GLUT inhibition is superior to single GLUT targeting. METHODS Glucose uptake and MTT/resazurin assays were used to measure DRB18's inhibitory activities of glucose transport and cell viability/proliferation in human lung cancer and other cancer cell lines. Four HEK293 cell lines expressing GLUT1-4 individually were used to determine the IC50 values of DRB18's inhibitory activity of glucose transport. Docking studies were performed to investigate the potential direct interaction of DRB18 with GLUT1-4. Metabolomics analysis was performed to identify metabolite changes in A549 lung cancer cells treated with DRB18. DRB18 was used to treat A549 tumor-bearing nude mice. The GLUT1 gene was knocked out to determine how the KO of the gene affected tumor growth. RESULTS DRB18 reduced glucose uptake mediated via each of GLUT1-4 with different IC50s, which match with the docking glidescores with a correlation coefficient of 0.858. Metabolomics analysis revealed that DRB18 altered energy-related metabolism in A549 cells by changing the abundance of metabolites in glucose-related pathways in vitro and in vivo. DRB18 eventually led to G1/S phase arrest and increased oxidative stress and necrotic cell death. IP injection of DRB18 in A549 tumor-bearing nude mice at 10 mg/kg body weight thrice a week led to a significant reduction in the tumor volume compared with mock-treated tumors. In contrast, the knockout of the GLUT1 gene did not reduce tumor volume. CONCLUSIONS DRB18 is a potent pan-class I GLUT inhibitor in vitro and in vivo in cancer cells. Mechanistically, it is likely to bind the outward open conformation of GLUT1-4, reducing tumor growth through inhibiting GLUT1-4-mediated glucose transport and metabolisms. Pan-class I GLUT inhibition is a better strategy than single GLUT targeting for inhibiting tumor growth.
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Affiliation(s)
- Pratik Shriwas
- Department of Biological Sciences, Ohio University, Athens, OH, 45701, USA.,Edison Biotechnology Institute, Ohio University, Athens, OH, 45701, USA.,Molecular and Cellular Biology Program, Ohio University, Athens, OH, 45701, USA.,Department of Biomedical Sciences, Ohio University, Athens, OH, 45701, USA
| | - Dennis Roberts
- Department of Chemistry and Biochemistry, Ohio University, Athens, OH, 45701, USA
| | - Yunsheng Li
- Edison Biotechnology Institute, Ohio University, Athens, OH, 45701, USA
| | - Liyi Wang
- Department of Chemistry and Biochemistry, Ohio University, Athens, OH, 45701, USA
| | - Yanrong Qian
- Edison Biotechnology Institute, Ohio University, Athens, OH, 45701, USA
| | - Stephen Bergmeier
- Molecular and Cellular Biology Program, Ohio University, Athens, OH, 45701, USA.,Department of Chemistry and Biochemistry, Ohio University, Athens, OH, 45701, USA.,Translational Biomedical Sciences Program, Ohio University, Athens, OH, 45701, USA
| | - Jennifer Hines
- Molecular and Cellular Biology Program, Ohio University, Athens, OH, 45701, USA.,Department of Chemistry and Biochemistry, Ohio University, Athens, OH, 45701, USA
| | - Subhodip Adhicary
- Department of Biological Sciences, Ohio University, Athens, OH, 45701, USA.,Translational Biomedical Sciences Program, Ohio University, Athens, OH, 45701, USA
| | - Corinne Nielsen
- Department of Biological Sciences, Ohio University, Athens, OH, 45701, USA.,Molecular and Cellular Biology Program, Ohio University, Athens, OH, 45701, USA.,Translational Biomedical Sciences Program, Ohio University, Athens, OH, 45701, USA
| | - Xiaozhuo Chen
- Department of Biological Sciences, Ohio University, Athens, OH, 45701, USA. .,Edison Biotechnology Institute, Ohio University, Athens, OH, 45701, USA. .,Molecular and Cellular Biology Program, Ohio University, Athens, OH, 45701, USA. .,Department of Biomedical Sciences, Ohio University, Athens, OH, 45701, USA. .,Department of Chemistry and Biochemistry, Ohio University, Athens, OH, 45701, USA. .,Edison Biotechnology Institute, Ohio University, 172 Water Tower Drive, Athens, OH, 43701, USA.
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20
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Wahl RL, Hicks RJ. PET Diagnosis and Response Monitoring in Oncology. Mol Imaging 2021. [DOI: 10.1016/b978-0-12-816386-3.00048-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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21
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Weits DA, van Dongen JT, Licausi F. Molecular oxygen as a signaling component in plant development. THE NEW PHYTOLOGIST 2021; 229:24-35. [PMID: 31943217 DOI: 10.1111/nph.16424] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 12/10/2019] [Indexed: 05/24/2023]
Abstract
While traditionally hypoxia has been studied as a detrimental component of flooding stress, the last decade has flourished with studies reporting the involvement of molecular oxygen availability in plant developmental processes. Moreover, proliferating and undifferentiated cells from different plant tissues were found to reside in endogenously generated hypoxic niches. Thus, stress-associated acute hypoxia may be distinguished from constitutively generated chronic hypoxia. The Cys/Arg branch of the N-degron pathway assumes a central role in integrating oxygen levels resulting in proteolysis of transcriptional regulators that control different aspects of plant growth and development. As a target of this pathway, group VII of the Ethylene Response Factor (ERF-VII) family has emerged as a hub for the integration of oxygen dynamics in root development and during seedling establishment. Additionally, vegetative shoot meristem activity and reproductive transition were recently associated with oxygen availability via two novel substrates of the N-degron pathways: VERNALISATION 2 (VRN2) and LITTLE ZIPPER 2 (ZPR2). Together, these observations support roles for molecular oxygen as a signalling molecule in plant development, as well as in essential metabolic reactions. Here, we review recent findings regarding oxygen-regulated development, and discuss outstanding questions that spring from these discoveries.
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Affiliation(s)
- Daan A Weits
- Plantlab, Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, 56010, Italy
| | | | - Francesco Licausi
- Plantlab, Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, 56010, Italy
- Biology Department, University of Pisa, Pisa, 56126, Italy
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22
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Sun L, Wang D, Zhang M, Jin Y, Jin B, Xu H, Du S, Xu Y, Zhao H, Lu X, Sang X, Zhong S, Yang H, Mao Y. Preoperative Immune Prognostic Index Can Predict the Clinical Outcomes of Patients with Gallbladder Cancer: Single-Center Experience. Cancer Manag Res 2020; 12:12137-12150. [PMID: 33269006 PMCID: PMC7701162 DOI: 10.2147/cmar.s271044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 11/10/2020] [Indexed: 12/14/2022] Open
Abstract
PURPOSE The immune prognostic index (IPI) has been used as a prognostic biomarker in various cancers. However, the prognostic value of the IPI in gallbladder cancer remains to be determined. PATIENTS AND METHODS This study included 139 patients who were diagnosed with gallbladder cancer after surgical resection from 2003 to 2017. We used a Kaplan-Meier curve analysis to evaluate the overall survival (OS). Cox proportional hazards regression methodology was used to identify significant independent prognostic factors. Prognostic nomograms for predicting OS were established to achieve superior discriminatory abilities. The prognostic nomograms were verified according to the concordance index, calibration curves, and decision curve analyses in the training cohort and validation cohort. RESULTS Of all 139 patients, 87 (62.6%) patients accepted R0 resection, 32% and 68% were stratified into the good and poor IPI group, respectively. The median OS was 55.9 (range, 5.93-182.7) months in the good IPI group and 15.47 (range, 0.29-190.37) months in the poor IPI group (P < 0.001). In the multivariate Cox model, the IPI was an independent predictor of OS along with the CA19-9, curative resection, and postoperative chemoradiotherapy. A nomogram based on these factors was efficient in predicting 1-, 3-, and 5-year survival probabilities. The nomogram showed higher sensitivity and specificity than the current cancer TNM staging system in the training cohort and validation cohort. CONCLUSION The IPI is an independent prognostic factor in gallbladder cancer. Our IPI-based nomogram can serve as a useful and convenient prognostic tool for gallbladder cancer.
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Affiliation(s)
- Lejia Sun
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing100730, People’s Republic of China
| | - Dongyue Wang
- Peking Union Medical College (PUMC), PUMC & Chinese Academy of Medical Sciences, Beijing100730, People’s Republic of China
| | - Mengyuan Zhang
- Peking Union Medical College (PUMC), PUMC & Chinese Academy of Medical Sciences, Beijing100730, People’s Republic of China
| | - Yukai Jin
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing100730, People’s Republic of China
| | - Bao Jin
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing100730, People’s Republic of China
| | - Haifeng Xu
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing100730, People’s Republic of China
| | - Shunda Du
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing100730, People’s Republic of China
| | - Yiyao Xu
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing100730, People’s Republic of China
| | - Haitao Zhao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing100730, People’s Republic of China
| | - Xin Lu
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing100730, People’s Republic of China
| | - Xinting Sang
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing100730, People’s Republic of China
| | - Shouxian Zhong
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing100730, People’s Republic of China
| | - Huayu Yang
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing100730, People’s Republic of China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Beijing100730, People’s Republic of China
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23
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Yu H, Yin Y, Yi Y, Cheng Z, Kuang W, Li R, Zhong H, Cui Y, Yuan L, Gong F, Wang Z, Li H, Peng H, Zhang G. Targeting lactate dehydrogenase A (LDHA) exerts antileukemic effects on T-cell acute lymphoblastic leukemia. Cancer Commun (Lond) 2020; 40:501-517. [PMID: 32820611 PMCID: PMC7571401 DOI: 10.1002/cac2.12080] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 07/07/2020] [Indexed: 12/29/2022] Open
Abstract
Background T‐cell acute lymphoblastic leukemia (T‐ALL) is an uncommon and aggressive subtype of acute lymphoblastic leukemia (ALL). In the serum of T‐ALL patients, the activity of lactate dehydrogenase A (LDHA) is increased. We proposed that targeting LDHA may be a potential strategy to improve T‐ALL outcomes. The current study was conducted to investigate the antileukemic effect of LDHA gene‐targeting treatment on T‐ALL and the underlying molecular mechanism. Methods Primary T‐ALL cell lines Jurkat and DU528 were treated with the LDH inhibitor oxamate. MTT, colony formation, apoptosis, and cell cycle assays were performed to investigate the effects of oxamate on T‐ALL cells. Quantitative real‐time PCR (qPCR) and Western blotting analyses were applied to determine the related signaling pathways. A mitochondrial reactive oxygen species (ROS) assay was performed to evaluate ROS production after T‐ALL cells were treated with oxamate. A T‐ALL transgenic zebrafish model with LDHA gene knockdown was established using CRISPR/Cas9 gene‐editing technology, and then TUNEL, Western blotting, and T‐ALL tumor progression analyses were conducted to investigate the effects of LDHA gene knockdown on T‐ALL transgenic zebrafish. Results Oxamate significantly inhibited proliferation and induced apoptosis of Jurkat and DU528 cells. It also arrested Jurkat and DU528 cells in G0/G1 phase and stimulated ROS production (all P < 0.001). Blocking LDHA significantly decreased the gene and protein expression of c‐Myc, as well as the levels of phosphorylated serine/threonine kinase (AKT) and glycogen synthase kinase 3 beta (GSK‐3β) in the phosphatidylinositol 3′‐kinase (PI3K) signaling pathway. LDHA gene knockdown delayed disease progression and down‐regulated c‐Myc mRNA and protein expression in T‐ALL transgenic zebrafish. Conclusion Targeting LDHA exerted an antileukemic effect on T‐ALL, representing a potential strategy for T‐ALL treatment.
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Affiliation(s)
- Haizhi Yu
- Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China.,Institute of Hematology, Central South University, Changsha, Hunan, 410011, P. R. China.,Department of Respiratory and Critical Medicine, NHC Key Laboratory of Pulmonary Immune-related Diseases, People's Hospital of Guizhou University, Guizhou Provincial People's Hospital, Guiyang, Guizhou, 550002, P. R. China
| | - Yafei Yin
- Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China.,Institute of Hematology, Central South University, Changsha, Hunan, 410011, P. R. China.,Department of Hematology, Xiangtan Central Hospital, Xiangtan, Hunan, 411100, P. R. China
| | - Yifang Yi
- Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China.,Institute of Hematology, Central South University, Changsha, Hunan, 410011, P. R. China.,Department of Hematology, Hunan Provincial People's Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, 410005, P. R. China
| | - Zhao Cheng
- Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China.,Institute of Hematology, Central South University, Changsha, Hunan, 410011, P. R. China
| | - Wenyong Kuang
- Department of Hematology, Hunan Children's Hospital, Changsha, Hunan, 410005, P. R. China
| | - Ruijuan Li
- Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China.,Institute of Hematology, Central South University, Changsha, Hunan, 410011, P. R. China
| | - Haiying Zhong
- Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China.,Institute of Hematology, Central South University, Changsha, Hunan, 410011, P. R. China
| | - Yajuan Cui
- Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China.,Institute of Hematology, Central South University, Changsha, Hunan, 410011, P. R. China
| | - Lingli Yuan
- Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China.,Institute of Hematology, Central South University, Changsha, Hunan, 410011, P. R. China
| | - Fanjie Gong
- Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China.,Institute of Hematology, Central South University, Changsha, Hunan, 410011, P. R. China
| | - Zhihua Wang
- Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China.,Institute of Hematology, Central South University, Changsha, Hunan, 410011, P. R. China
| | - Heng Li
- Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China.,Institute of Hematology, Central South University, Changsha, Hunan, 410011, P. R. China
| | - Hongling Peng
- Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China.,Institute of Hematology, Central South University, Changsha, Hunan, 410011, P. R. China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, Changsha, Hunan, 410011, P. R. China
| | - Guangsen Zhang
- Department of Hematology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China.,Institute of Hematology, Central South University, Changsha, Hunan, 410011, P. R. China
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Gray A, Dang BN, Moore TB, Clemens R, Pressman P. A review of nutrition and dietary interventions in oncology. SAGE Open Med 2020; 8:2050312120926877. [PMID: 32537159 PMCID: PMC7268120 DOI: 10.1177/2050312120926877] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 04/22/2020] [Indexed: 12/11/2022] Open
Abstract
The complex cellular mechanisms and inter-related pathways of cancer proliferation, evasion, and metastasis remain an emerging field of research. Over the last several decades, nutritional research has prominent role in identifying emerging adjuvant therapies in our fight against cancer. Nutritional and dietary interventions are being explored to improve the morbidity and mortality for cancer patients worldwide. In this review, we examine several dietary interventions and their proposed mechanisms against cancer as well as identifying limitations in the currently available literature. This review provides a comprehensive review of the cancer metabolism, dietary interventions used during cancer treatment, anti metabolic drugs, and their impact on nutritional deficiencies along with a critical review of the following diets: caloric restriction, intermittent fasting, ketogenic diet, Mediterranean diet, Japanese diet, and vegan diet.
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Affiliation(s)
- Ashley Gray
- Division of Pediatric Hematology/Oncology, Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Brian N Dang
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Theodore B Moore
- Division of Pediatric Hematology/Oncology, Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Roger Clemens
- Pharmacology & Pharmaceutical Sciences, USC School of Pharmacy, International Center for Regulatory Science, Los Angeles, CA, USA
| | - Peter Pressman
- Polyscience Consulting & Director of Nutrition and Public Health, The Daedalus Foundation, San Clemente, CA, USA
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25
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Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives. Cells 2020; 9:cells9030596. [PMID: 32138158 PMCID: PMC7140515 DOI: 10.3390/cells9030596] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 02/24/2020] [Accepted: 02/26/2020] [Indexed: 12/14/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a deadly tumor without an effective therapy. Unique metabolic and bioenergetics features are important hallmarks of tumor cells. Metabolic plasticity allows cancer cells to survive in poor nutrient environments and maximize cell growth by sustaining survival, proliferation, and metastasis. In recent years, an increasing number of studies have shown that specific signaling networks contribute to malignant tumor onset by reprogramming metabolic traits. Several evidences demonstrate that numerous metabolic mediators represent key-players of CCA progression by regulating many signaling pathways. Besides the well-known Warburg effect, several other different pathways involving carbohydrates, proteins, lipids, and nucleic acids metabolism are altered in CCA. The goal of this review is to highlight the main metabolic processes involved in the cholangio-carcinogeneis that might be considered as potential novel druggable candidates for this disease.
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26
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Muniraj N, Siddharth S, Nagalingam A, Walker A, Woo J, Győrffy B, Gabrielson E, Saxena NK, Sharma D. Withaferin A inhibits lysosomal activity to block autophagic flux and induces apoptosis via energetic impairment in breast cancer cells. Carcinogenesis 2019; 40:1110-1120. [PMID: 30698683 PMCID: PMC10893887 DOI: 10.1093/carcin/bgz015] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 01/02/2019] [Accepted: 01/22/2019] [Indexed: 12/24/2022] Open
Abstract
Withaferin A (WFA), a steroidal lactone, negatively regulates breast cancer growth however, its mechanisms of action remain largely elusive. We found that WFA blocks autophagy flux and lysosomal proteolytic activity in breast cancer cells. WFA increases accumulation of autophagosomes, LC3B-II conversion, expression of autophagy-related proteins and autophagosome/lysosome fusion. Autolysosomes display the characteristics of acidic compartments in WFA-treated cells; however, the protein degradation activity of lysosomes is inhibited. Blockade of autophagic flux reduces the recycling of cellular fuels leading to insufficient substrates for tricarboxylic acid (TCA) cycle and impaired oxidative phosphorylation. WFA decreases expression and phosphorylation of lactate dehydrogenase, the key enzyme that catalyzes pyruvate-to-lactate conversion, reduces adenosine triphosphate levels and increases AMP-activated protein kinase (AMPK) activation. AMPK inhibition abrogates while AMPK activation potentiates WFA's effect. WFA and 2-deoxy-d-glucose combination elicits synergistic inhibition of breast cancer cells. Genetic knockout of BECN1 and ATG7 fails to rescue cells from WFA treatment; in contrast, addition of methyl pyruvate to supplement TCA cycle protects WFA-treated cells. Together, these results implicate that WFA is a potent lysosomal inhibitor; energetic impairment is required for WFA-induced apoptosis and growth inhibition and combining WFA and 2-DG is a promising therapeutic strategy for breast cancer.
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Affiliation(s)
- Nethaji Muniraj
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sumit Siddharth
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Arumugam Nagalingam
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alyssa Walker
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Juhyung Woo
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Balázs Győrffy
- MTA TTK Momentum Cancer Biomarker Research Group, Budapest, Hungary
- 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Ed Gabrielson
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Neeraj K Saxena
- Early Detection Research Group, National Cancer Institute, Rockville, MD, USA
| | - Dipali Sharma
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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27
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Machilin A Inhibits Tumor Growth and Macrophage M2 Polarization Through the Reduction of Lactic Acid. Cancers (Basel) 2019; 11:cancers11070963. [PMID: 31324019 PMCID: PMC6678097 DOI: 10.3390/cancers11070963] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 06/28/2019] [Accepted: 07/05/2019] [Indexed: 12/19/2022] Open
Abstract
Lactate dehydrogenase A (LDHA) is an important enzyme responsible for cancer growth and energy metabolism in various cancers via the aerobic glycolytic pathway. Here, we report that machilin A (MA), which acts as a competitive inhibitor by blocking the nicotinamide adenine dinucleotide (NAD) binding site of LDHA, suppresses growth of cancer cells and lactate production in various cancer cell types, including colon, breast, lung, and liver cancers. Furthermore, MA markedly decreased LDHA activity, lactate production, and intracellular adenosine triphosphate (ATP) levels induced by hypoxia-induced LDHA expression in cancer cells, and significantly inhibited colony formation, leading to reduced cancer cell survival. In mouse models inoculated with murine Lewis lung carcinoma, MA significantly suppressed tumor growth as observed by a reduction of tumor volume and weight; resulting from the inhibition of LDHA activity. Subsequently, the suppression of tumor-derived lactic acid in MA-treated cancer cells resulted in decrease of neovascularization through the regulation of alternatively activated macrophages (M2) polarization in macrophages. Taken together, we suggest that the reduction of lactate by MA in cancer cells directly results in a suppression of cancer cell growth. Furthermore, macrophage polarization and activation of endothelial cells for angiogenesis were indirectly regulated preventing lactate production in MA-treated cancer cells.
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28
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Abstract
Development of novel and effective therapeutics for treating various cancers is probably the most congested and challenging enterprise of pharmaceutical companies. Diverse drugs targeting malignant and nonmalignant cells receive clinical approval each year from the FDA. Targeting cancer cells and nonmalignant cells unavoidably changes the tumor microenvironment, and cellular and molecular components relentlessly alter in response to drugs. Cancer cells often reprogram their metabolic pathways to adapt to environmental challenges and facilitate survival, proliferation, and metastasis. While cancer cells' dependence on glycolysis for energy production is well studied, the roles of adipocytes and lipid metabolic reprogramming in supporting cancer growth, metastasis, and drug responses are less understood. This Review focuses on emerging mechanisms involving adipocytes and lipid metabolism in altering the response to cancer treatment. In particular, we discuss mechanisms underlying cancer-associated adipocytes and lipid metabolic reprogramming in cancer drug resistance.
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29
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Bernfeld E, Foster DA. Glutamine as an Essential Amino Acid for KRas-Driven Cancer Cells. Trends Endocrinol Metab 2019; 30:357-368. [PMID: 31040047 DOI: 10.1016/j.tem.2019.03.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 03/24/2019] [Accepted: 03/25/2019] [Indexed: 01/07/2023]
Abstract
Cancer cells consume glutamine, a nonessential amino acid (NEAA), at exceedingly high rates to fulfill their energetic and biosynthetic requirements for proliferation. Glutamine plays distinct roles from essential amino acids in cell cycle progression and in the activation of mammalian target of rapamycin (mTOR). Furthermore, the need of cancer cells for glutamine can be exploited therapeutically - especially those driven by KRas. In this review we explore several distinct cellular roles for glutamine that contribute to glutamine addiction in KRas-driven cancer cells and discuss opportunities for therapeutic intervention created by glutamine addiction.
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Affiliation(s)
- Elyssa Bernfeld
- Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA; Biochemistry PhD Program, The Graduate Center, City University of New York, New York, NY, USA; Current address: Oncology R&D Group, Pfizer Worldwide Research and Development, 401 N. Middletown Road, Pearl River, NY, USA
| | - David A Foster
- Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA; Biochemistry PhD Program, The Graduate Center, City University of New York, New York, NY, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
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30
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Dayan A, Fleminger G, Ashur-Fabian O. Targeting the Achilles’ heel of cancer cells via integrin-mediated delivery of ROS-generating dihydrolipoamide dehydrogenase. Oncogene 2019; 38:5050-5061. [DOI: 10.1038/s41388-019-0775-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 02/03/2019] [Accepted: 02/19/2019] [Indexed: 12/18/2022]
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31
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Kerpen L, Niccolini L, Licausi F, van Dongen JT, Weits DA. Hypoxic Conditions in Crown Galls Induce Plant Anaerobic Responses That Support Tumor Proliferation. FRONTIERS IN PLANT SCIENCE 2019; 10:56. [PMID: 30804956 PMCID: PMC6371838 DOI: 10.3389/fpls.2019.00056] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 01/16/2019] [Indexed: 05/21/2023]
Abstract
Agrobacterium tumefaciens infection of wounded plant tissues causes the formation of crown gall tumors. Upon infection, genes encoded on the A. tumefaciens tumor inducing plasmid are integrated in the plant genome to induce the biosynthesis of auxin and cytokinin, leading to uncontrolled cell division. Additional sequences present on the bacterial T-DNA encode for opine biosynthesis genes, which induce the production of opines that act as a unique carbon and nitrogen source for Agrobacterium. Crown galls therefore become a very strong sink for photosynthate. Here we found that the increased metabolic demand in crown galls causes an increase in oxygen consumption rate, which leads to a steep drop in the internal oxygen concentration. Consistent with this, plant hypoxia-responsive genes were found to be significantly upregulated in crown galls compared to uninfected stem tissue. Following this observation, we aimed at understanding whether the low-oxygen response pathway, mediated by group VII ethylene response factor (ERF-VII) transcription factors, plays a role in the development of crown galls. We found that quintuple knock-out mutants of all ERF-VII members, which are incapable of inducing the hypoxic response, show reduced crown gall symptoms. Conversely, mutant genotypes characterized by constitutively high levels of hypoxia-associated transcripts, displayed more severe crown gall symptoms. Based on these results, we concluded that uncontrolled cell proliferation of crown galls established hypoxic conditions, thereby requiring adequate anaerobic responses of the plant tissue to support tumor growth.
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Affiliation(s)
- Lucy Kerpen
- Institute of Biology I, RWTH Aachen University, Aachen, Germany
| | | | - Francesco Licausi
- Department of Biology, University of Pisa, Pisa, Italy
- Scuola Superiore Sant’Anna, Institute of Life Sciences, Pisa, Italy
| | | | - Daan A. Weits
- Institute of Biology I, RWTH Aachen University, Aachen, Germany
- Scuola Superiore Sant’Anna, Institute of Life Sciences, Pisa, Italy
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32
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Shukla SK, Mulder SE, Singh PK. Hypoxia-Mediated In Vivo Tumor Glucose Uptake Measurement and Analysis. Methods Mol Biol 2019; 1742:107-113. [PMID: 29330794 DOI: 10.1007/978-1-4939-7665-2_10] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Most solid tumors are hypoxic in nature due to the limited supply of oxygen to internal tissues. Hypoxia plays an important role in metabolic adaptations of tumors that contribute significantly to cancer pathogenesis. Among the several metabolic alterations induced by hypoxia, hypoxia-mediated increased glucose uptake serves as the hallmark of metabolic reprogramming. Hypoxia-mediated stabilization of hypoxia-inducible factor-1 alpha (HIF-1α) transcription factor leads to altered expression of several glycolytic genes and glucose transporters, which results in increased glucose uptake by tumor cells. Here we describe an easy and simple way of measuring the hypoxia-mediated tumor glucose uptake in vivo. The method is based on fluorescent imaging probe, RediJect 2-DG, which is a nonradioactive fluorescent-tagged glucose molecule. We have discussed orthotopic tumor implantation of HIF-1α knockdown and control pancreatic cancer cells and glucose uptake measurement in vivo by using IVIS imaging system along with reagent preparations.
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Affiliation(s)
- Surendra K Shukla
- The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Scott E Mulder
- The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Pankaj K Singh
- The Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
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33
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Ruan L, Zhou M, Chen J, Huang H, Zhang J, Sun H, Chai Z, Hu Y. Thermoresponsive drug delivery to mitochondria in vivo. Chem Commun (Camb) 2019; 55:14645-14648. [DOI: 10.1039/c9cc07538k] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Thermoresponsive drug delivery to mitochondria in a mouse model of cancer.
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Affiliation(s)
- Lifo Ruan
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety
- Multidisciplinary Research Division
- Institute of High Energy Physics
- Chinese Academy of Sciences (CAS)
- Beijing 100049
| | - Mengxue Zhou
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety
- Multidisciplinary Research Division
- Institute of High Energy Physics
- Chinese Academy of Sciences (CAS)
- Beijing 100049
| | - Jun Chen
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety
- Multidisciplinary Research Division
- Institute of High Energy Physics
- Chinese Academy of Sciences (CAS)
- Beijing 100049
| | - Hui Huang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety
- Multidisciplinary Research Division
- Institute of High Energy Physics
- Chinese Academy of Sciences (CAS)
- Beijing 100049
| | - Jiayu Zhang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety
- Multidisciplinary Research Division
- Institute of High Energy Physics
- Chinese Academy of Sciences (CAS)
- Beijing 100049
| | - Hongyan Sun
- Department of Chemistry and COSDAF (Centre of Super-Diamond and Advanced Films)
- City University of Hong Kong
- Kowloon
- China
| | - Zhifang Chai
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety
- Multidisciplinary Research Division
- Institute of High Energy Physics
- Chinese Academy of Sciences (CAS)
- Beijing 100049
| | - Yi Hu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety
- Multidisciplinary Research Division
- Institute of High Energy Physics
- Chinese Academy of Sciences (CAS)
- Beijing 100049
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34
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Wang G, Wang JJ, Guan R, Sun Y, Shi F, Gao J, Fu XL. Targeting Strategies for Glucose Metabolic Pathways and T Cells in Colorectal Cancer. Curr Cancer Drug Targets 2018; 19:534-550. [PMID: 30360743 DOI: 10.2174/1568009618666181015150138] [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: 04/07/2017] [Revised: 11/23/2017] [Accepted: 12/24/2017] [Indexed: 11/22/2022]
Abstract
Colorectal cancer is a heterogeneous group of diseases that result from the accumulation of different sets of genomic alterations, together with epigenomic alterations, and it is influenced by tumor-host interactions, leading to tumor cell growth and glycolytic imbalances. This review summarizes recent findings that involve multiple signaling molecules and downstream genes in the dysregulated glycolytic pathway. This paper further discusses the role of the dysregulated glycolytic pathway in the tumor initiation, progression and the concomitant systemic immunosuppression commonly observed in colorectal cancer patients. Moreover, the relationship between colorectal cancer cells and T cells, especially CD8+ T cells, is discussed, while different aspects of metabolic pathway regulation in cancer cell proliferation are comprehensively defined. Furthermore, this study elaborates on metabolism in colorectal cancer, specifically key metabolic modulators together with regulators, glycolytic enzymes, and glucose deprivation induced by tumor cells and how they inhibit T-cell glycolysis and immunogenic functions. Moreover, metabolic pathways that are integral to T cell function, differentiation, and activation are described. Selective metabolic inhibitors or immunemodulation agents targeting these pathways may be clinically useful to increase effector T cell responses for colorectal cancer treatment. However, there is a need to identify specific antigens using a cancer patient-personalized approach and combination strategies with other therapeutic agents to effectively target tumor metabolic pathways.
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Affiliation(s)
- Gang Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, 200235, Shanghai, China
| | - Jun-Jie Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, 200235, Shanghai, China
| | - Rui Guan
- Hubei University of Medicine, NO. 30 People South Road, Shiyan City, Hubei Province 442000, China
| | - Yan Sun
- Hubei University of Medicine, NO. 30 People South Road, Shiyan City, Hubei Province 442000, China
| | - Feng Shi
- Department of Medicine, Jiangsu University, Zhenjiang City, Jiangsu Province 212001, China
| | - Jing Gao
- Department of Medicine, Jiangsu University, Zhenjiang City, Jiangsu Province 212001, China
| | - Xing-Li Fu
- Department of Medicine, Jiangsu University, Zhenjiang City, Jiangsu Province 212001, China
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35
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Verma A, Lam YM, Leung YC, Hu X, Chen X, Cheung E, Tam KY. Combined use of arginase and dichloroacetate exhibits anti-proliferative effects in triple negative breast cancer cells. J Pharm Pharmacol 2018; 71:306-315. [DOI: 10.1111/jphp.13033] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 09/29/2018] [Indexed: 12/23/2022]
Abstract
Abstract
Objectives
Drug combination in cancer therapy aims to achieve synergistic therapeutic effect, reduced drug dosage, reduced drug toxicity and minimizes or delays the induction of drug resistance. In the present study, we investigated the anticancer effects of the combination of two metabolic modulators, dichloroacetate (DCA) and bacillus caldovelox arginase (BCA) (or pegyated human arginase (HA)).
Methods
The combination treatments were evaluated in MCF-7 and MDA-MB 231 cells as well as in MDA-MB 231 breast cancer xenograft model.
Key findings
Dichloroacetate and BCA combination exhibited anti-proliferative effects on MCF-7 cells, which were found to be synergistic. Analysis of the gene expression upon drug treatments revealed that the synergistic anti-proliferative effect on MCF-7 cells was possibly in part due to the activation of the p53 pathway. A similar synergistic anti-proliferative effect was observed in the combined use of DCA and HA on MCF-7 and MDA-MB231 cells, which was due to induction of cell cycle arrest at G2/M phase. Moreover, the combination enhanced anti-tumour activity in a MDA-MB 231 xenograft mouse model.
Conclusions
Our results suggested that dichloroacetate and arginase combination exhibited enhanced anti-cancer effects in preclinical breast cancer models which may offer an additional treatment option for breast cancer.
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Affiliation(s)
- Angela Verma
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Yau-Min Lam
- Department of Applied Biology and Chemical Technology, Lo Ka Chung Centre for Natural Anti-Cancer Drug Development, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
| | - Yun-Chung Leung
- Department of Applied Biology and Chemical Technology, Lo Ka Chung Centre for Natural Anti-Cancer Drug Development, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
| | - Xiaohui Hu
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Xin Chen
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Edwin Cheung
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
| | - Kin Yip Tam
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China
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Miranda-Gonçalves V, Lameirinhas A, Henrique R, Jerónimo C. Metabolism and Epigenetic Interplay in Cancer: Regulation and Putative Therapeutic Targets. Front Genet 2018; 9:427. [PMID: 30356832 PMCID: PMC6190739 DOI: 10.3389/fgene.2018.00427] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 09/10/2018] [Indexed: 12/31/2022] Open
Abstract
Alterations in the epigenome and metabolism affect molecular rewiring of cancer cells facilitating cancer development and progression. Modulation of histone and DNA modification enzymes occurs owing to metabolic reprogramming driven by oncogenes and expression of metabolism-associated genes is, in turn, epigenetically regulated, promoting the well-known metabolic reprogramming of cancer cells and, consequently, altering the metabolome. Thus, several malignant traits are supported by the interplay between metabolomics and epigenetics, promoting neoplastic transformation. In this review we emphasize the importance of tumour metabolites in the activity of most chromatin-modifying enzymes and implication in neoplastic transformation. Furthermore, candidate targets deriving from metabolism of cancer cells and altered epigenetic factors is emphasized, focusing on compounds that counteract the epigenomic-metabolic interplay in cancer.
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Affiliation(s)
- Vera Miranda-Gonçalves
- Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal
| | - Ana Lameirinhas
- Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal.,Master in Oncology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Rui Henrique
- Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal.,Department of Pathology, Portuguese Oncology Institute of Porto, Porto, Portugal.,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Porto, Portugal.,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
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Choromanska A, Lubinska S, Szewczyk A, Saczko J, Kulbacka J. Mechanisms of antimelanoma effect of oat β-glucan supported by electroporation. Bioelectrochemistry 2018; 123:255-259. [DOI: 10.1016/j.bioelechem.2018.06.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 05/19/2018] [Accepted: 06/05/2018] [Indexed: 10/14/2022]
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Zhang H, Li L, Chen Q, Li M, Feng J, Sun Y, Zhao R, Zhu Y, Lv Y, Zhu Z, Huang X, Xie W, Xiang W, Yao P. PGC1β regulates multiple myeloma tumor growth through LDHA-mediated glycolytic metabolism. Mol Oncol 2018; 12:1579-1595. [PMID: 30051603 PMCID: PMC6120252 DOI: 10.1002/1878-0261.12363] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 06/16/2018] [Accepted: 07/03/2018] [Indexed: 12/13/2022] Open
Abstract
Multiple myeloma (MM) is an incurable hematologic malignancy due to inevitable relapse and chemoresistance development. Our preliminary data show that MM cells express high levels of PGC1β and LDHA. In this study, we investigated the mechanism behind PGC1β‐mediated LDHA expression and its contribution to tumorigenesis, to aid in the development of novel therapeutic approaches for MM. Real‐time PCR and western blotting were first used to evaluate gene expression of PGC1β and LDHA in different MM cells, and then, luciferase reporter assay, chromatin immunoprecipitation, LDHA deletion report vectors, and siRNA techniques were used to investigate the mechanism underlying PGC1β‐induced LDHA expression. Furthermore, knockdown cell lines and lines stably overexpressing PGC1β or LDHA lentivirus were established to evaluate in vitro glycolysis metabolism, mitochondrial function, reactive oxygen species (ROS) formation, and cell proliferation. In addition, in vivo xenograft tumor development studies were performed to investigate the effect of PGC1β or LDHA expression on tumor growth and mouse survival. We found that PGC1β and LDHA are highly expressed in different MM cells and LDHA is upregulated by PGC1β through the PGC1β/RXRβ axis acting on the LDHA promoter. Overexpression of PGC1β or LDHA significantly potentiated glycolysis metabolism with increased cell proliferation and tumor growth. On the other hand, knockdown of PGC1β or LDHA largely suppressed glycolysis metabolism with increased ROS formation and apoptosis rate, in addition to suppressing tumor growth and enhancing mouse survival. This is the first time the mechanism underlying PGC1β‐mediated LDHA expression in multiple myeloma has been identified. We conclude that PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism. Targeting the PGC1β/LDHA pathway may be a novel therapeutic strategy for multiple myeloma treatment.
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Affiliation(s)
- Hongyu Zhang
- Department of Hematology, Peking University Shenzhen Hospital, China
| | - Ling Li
- Department of Pediatrics, Hainan Maternal and Child Health Hospital, Haikou, China
| | - Qi Chen
- Department of Hematology, Peking University Shenzhen Hospital, China
| | - Min Li
- Institute of Rehabilitation Center, Tongren Hospital of Wuhan University, China
| | - Jia Feng
- Department of Hematology, Peking University Shenzhen Hospital, China
| | - Ying Sun
- Department of Pediatrics, Hainan Maternal and Child Health Hospital, Haikou, China
| | - Rong Zhao
- Institute of Rehabilitation Center, Tongren Hospital of Wuhan University, China
| | - Yin Zhu
- Department of Geriatrics, National Key Clinical Specialty, Guangzhou First People's Hospital, Guangzhou Medical University, China
| | - Yang Lv
- Department of Pediatrics, Hainan Maternal and Child Health Hospital, Haikou, China
| | - Zhigang Zhu
- Department of Geriatrics, National Key Clinical Specialty, Guangzhou First People's Hospital, Guangzhou Medical University, China
| | - Xiaodong Huang
- Institute of Rehabilitation Center, Tongren Hospital of Wuhan University, China
| | - Weiguo Xie
- Institute of Rehabilitation Center, Tongren Hospital of Wuhan University, China
| | - Wei Xiang
- Department of Pediatrics, Hainan Maternal and Child Health Hospital, Haikou, China
| | - Paul Yao
- Department of Hematology, Peking University Shenzhen Hospital, China.,Department of Pediatrics, Hainan Maternal and Child Health Hospital, Haikou, China.,Institute of Rehabilitation Center, Tongren Hospital of Wuhan University, China
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Lee J, Lee WK, Seol MY, Lee SG, Kim D, Kim H, Park J, Jung SG, Chung WY, Lee EJ, Jo YS. Coupling of LETM1 up-regulation with oxidative phosphorylation and platelet-derived growth factor receptor signaling via YAP1 transactivation. Oncotarget 2018; 7:66728-66739. [PMID: 27556512 PMCID: PMC5341833 DOI: 10.18632/oncotarget.11456] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 08/13/2016] [Indexed: 02/04/2023] Open
Abstract
Persistent cellular proliferation and metabolic reprogramming are essential processes in carcinogenesis. Here, we performed Gene Set Enrichment Analysis (GSEA) and found that that LETM1, a mitochondrial calcium transporter, is associated with cellular growth signals such as platelet-derived growth factor (PDGF) receptor signaling and insulin signaling pathways. These results were then verified by qRT-PCR and immnunoblotting. Mechanistically, up-regulation of LETM1 induced YAP1 nuclear accumulation, increasing the expression of PDGFB, PDGFRB and THBS4. Consistent with this, LETM1 silencing caused loss of YAP1 nuclear signal, decreasing the expression of PDGFB, PDGFRB and THBS4. Immunohistochemical staining consistently indicated a positive association between LETM1 up-regulation, YAP1 nuclear localization and high PDGFB expression. In clinical data analysis, LETM1 up-regulation in thyroid cancer was found to be related to aggressive tumor features such as lymphovascular invasion (LVI, P < 0.001) and lymph node metastasis (LNM, P = 0.011). Multivariate analysis demonstrated that LETM1 up-regulation increases the risk of LVI and LNM (OR = 3.455, 95% CI = 1.537–7.766 and OR = 3.043, 95% CI = 1.282–7.225, respectively). Collectively, these data suggest that up-regulation of LETM1 induces sustained activation of proliferative signaling pathways, such as PDGF signal pathway by AKT induced YAP1 transactivation, resulting in aggressive thyroid cancer phenotypes.
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Affiliation(s)
- Jandee Lee
- Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Woo Kyung Lee
- Department of Internal Medicine, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Mi-Youn Seol
- Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Seul Gi Lee
- Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Daham Kim
- Department of Internal Medicine, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Hyunji Kim
- Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jongsun Park
- Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, Korea
| | - Sang Geun Jung
- Department of Gynecological Oncology, Bundang CHA Medical Center, CHA University, Gyeonggi-do, Korea
| | - Woong Youn Chung
- Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Jig Lee
- Department of Internal Medicine, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Young Suk Jo
- Department of Internal Medicine, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
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40
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Hofmann P. Cancer and Exercise: Warburg Hypothesis, Tumour Metabolism and High-Intensity Anaerobic Exercise. Sports (Basel) 2018; 6:sports6010010. [PMID: 29910314 PMCID: PMC5969185 DOI: 10.3390/sports6010010] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 01/24/2018] [Accepted: 01/29/2018] [Indexed: 12/22/2022] Open
Abstract
There is ample evidence that regular moderate to vigorous aerobic physical activity is related to a reduced risk for various forms of cancer to suggest a causal relationship. Exercise is associated with positive changes in fitness, body composition, and physical functioning as well as in patient-reported outcomes such as fatigue, sleep quality, or health-related quality of life. Emerging evidence indicates that exercise may also be directly linked to the control of tumour biology through direct effects on tumour-intrinsic factors. Beside a multitude of effects of exercise on the human body, one underscored effect of exercise training is to target the specific metabolism of tumour cells, namely the Warburg-type highly glycolytic metabolism. Tumour metabolism as well as the tumour–host interaction may be selectively influenced by single bouts as well as regularly applied exercise, dependent on exercise intensity, duration, frequency and mode. High-intensity anaerobic exercise was shown to inhibit glycolysis and some studies in animals showed that effects on tumour growth might be stronger compared with moderate-intensity aerobic exercise. High-intensity exercise was shown to be safe in patients; however, it has to be applied carefully with an individualized prescription of exercise.
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Affiliation(s)
- Peter Hofmann
- Institute of Sports Sciences, Exercise Physiology, Training & Training Therapy Research Group, University of Graz, Max Mell Allee 11, Graz 8010, Austria.
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41
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MiR-34b-3 and miR-449a inhibit malignant progression of nasopharyngeal carcinoma by targeting lactate dehydrogenase A. Oncotarget 2018; 7:54838-54851. [PMID: 27458165 PMCID: PMC5342385 DOI: 10.18632/oncotarget.10761] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 07/06/2016] [Indexed: 12/19/2022] Open
Abstract
MicroRNA expression profiling assays have shown that miR-34b/c and miR-449a are down-regulated in nasopharyngeal carcinoma (NPC); however, the targets and functions of miR-34b/c and miR-449a in the pathologenesis of NPC remain elusive. In this study, we verified miR-34b/c and miR-449a were significantly reduced with the advance of NPC. Overexpression of miR-34b-3 and miR-449a suppressed the growth of NPC cells in culture and mouse tumor xenografts. Using tandem mass tags for quantitative labeling and LC-MS/MS analysis to investigate protein changes after restoring expression of miR-34b-3, 251 proteins were found to be down-regulated after miR-34b-3 transfection. Through 3 replicate experiments, we found that miR-34b-3 regulated the expression of 15 potential targeted genes mainly clustered in the key enzymes of glycolysis metabolism, including lactate dehydrogenase A (LDHA). Further investigation revealed that miR-34b-3 and miR-449a negatively regulated LDHA by binding to the 3′ untranslated regions of LDHA. Furthermore, LDHA overexpression rescued the miR-34b-3 and miR-449a induced tumor inhibition effect in CNE2 cells. In addition, miR-34b-3 and miR-449a suppressed LDH activity and reduced LD content, which were directly induced by downregulation of the LDHA. Our findings suggest that miR-34b-3 and miR-449a suppress the development of NPC through regulation of glycolysis via targeting LDHA and may be potential therapeutic targets for the treatment of NPC.
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miR-200b is a key regulator of tumor progression and metabolism targeting lactate dehydrogenase A in human malignant glioma. Oncotarget 2018; 7:48423-48431. [PMID: 27374173 PMCID: PMC5217028 DOI: 10.18632/oncotarget.10301] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 06/04/2016] [Indexed: 11/25/2022] Open
Abstract
Lactate dehydrogenase A (LDHA) is involved in various cancers. In this study, we investigated the expression and function of LDHA in glioma. We found that LDHA was up-regulated in glioma samples. Furthermore, we found that overexpression of LDHA promoted proliferation, invasion and glycolysis in glioma cells. Luciferase reporter assays confirmed that LDHA was a direct target of miR-200b. miR-200b was found to be down-regulated in glioma samples, which was inversely correlated with LDHA expression. Repression of LDHA by miR-200b suppressed the glycolysis, cell proliferation and invasion of glioma cells. These results provide evidence that miR-200b acts as a tumor suppressor in glioma through the inhibition of LDHA both in vitro and in vivo. Targeting LDHA through miR-200b could be a potential therapeutic strategy in glioma.
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43
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WITHDRAWN: Mechanisms of antimelanoma effect of oat β-glucan supported by electroporation. Bioelectrochemistry 2018. [DOI: 10.1016/j.bioelechem.2018.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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44
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Hirani A, Grover A, Lee YW, Pathak Y, Sutariya V. Nanotechnology for Omics-Based Ocular Drug Delivery. Ophthalmology 2018. [DOI: 10.4018/978-1-5225-5195-9.ch017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Millions of people suffer from ocular diseases that impair vision and can lead to blindness. Advances in genomics and proteomics have revealed a number of different molecular markers specific for different ocular diseases, thereby optimizing the processes of drug development and discovery. Nanotechnology can increase the throughput of data obtained in omics-based studies and allows for more sensitive diagnostic techniques as more efficient drug delivery systems. Biocompatible and biodegradable nanomaterials developed through omics-based research are able to target reported molecular markers for different ocular diseases and offer novel alternatives to conventional drug therapy. In this chapter, the authors review the pathophysiology, current genomic and proteomic information, and current nanomaterial-based therapies of four ocular diseases: glaucoma, uveal melanoma, age-related macular degeneration, and diabetic retinopathy. Omics-based research can be used to elucidate specific genes and proteins and develop novel nanomedicine formulations to prevent, halt, or cure ocular diseases at the transcriptional or translational level.
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Affiliation(s)
- Anjali Hirani
- University of South Florida, USA & Virginia Tech-Wake Forest University, USA
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45
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Kim SL, Lee ST, Min IS, Park YR, Lee JH, Kim DG, Kim SW. Lipocalin 2 negatively regulates cell proliferation and epithelial to mesenchymal transition through changing metabolic gene expression in colorectal cancer. Cancer Sci 2017; 108:2176-2186. [PMID: 28859238 PMCID: PMC5666039 DOI: 10.1111/cas.13389] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 08/20/2017] [Accepted: 08/25/2017] [Indexed: 12/17/2022] Open
Abstract
Lipocalin 2 (LCN2), a member of the lipocalin superfamily, plays an important role in oncogenesis and progression in various types of cancer. However, the expression pattern and functional role of LCN2 in colorectal cancer (CRC) is still poorly understood. The purpose of the present study was to investigate whether LCN2 is associated with proliferation and the epithelial-mesenchymal transition (EMT) in CRC and to elucidate the underlying signaling pathways. LCN2 was preferentially expressed in CRC cells compared to normal tissues. However, LCN2 expression was significantly lower in metastatic or advanced-stage CRC than in non-metastatic or early stage CRC. Knockdown of LCN2 using small interfering RNA (siRNA) in CRC cells expressing a high level of LCN2 induced cell proliferation and a morphological switch from an epithelial to mesenchymal state. Furthermore, downregulation of LCN2 in CRC cells increased cell migration and invasion involved in the regulation of EMT markers. Knockdown of LCN2 also induced glucose consumption and lactate production, accompanied by an increase in energy metabolism-related genes. Taken together, our findings indicated that LCN2 negatively modulated proliferation, EMT and energy metabolism in CRC cells. Accordingly, LCN2 may be a candidate metastasis suppressor and potential therapeutic target in CRC.
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Affiliation(s)
- Se-Lim Kim
- Department of Internal Medicine Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea.,Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Soo Teik Lee
- Department of Internal Medicine Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea.,Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - In Suk Min
- Department of Internal Medicine Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea.,Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Young Ran Park
- Department of Internal Medicine Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea.,Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Ju Hyung Lee
- Department of Preventive Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Dae-Ghon Kim
- Department of Internal Medicine Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea.,Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Sang-Wook Kim
- Department of Internal Medicine Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea.,Biomedical Research Institute, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
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Jin L, Chun J, Pan C, Alesi GN, Li D, Magliocca KR, Kang Y, Chen ZG, Shin DM, Khuri FR, Fan J, Kang S. Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis. Oncogene 2017; 36:3797-3806. [PMID: 28218905 PMCID: PMC5501759 DOI: 10.1038/onc.2017.6] [Citation(s) in RCA: 208] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 12/12/2016] [Accepted: 01/12/2017] [Indexed: 12/14/2022]
Abstract
Metastases remain the major cause of death from cancer. Recent molecular advances have highlighted the importance of metabolic alterations in cancer cells, including the Warburg effect that describes an increased glycolysis in cancer cells. However, how this altered metabolism contributes to tumour metastasis remains elusive. Here, we report that phosphorylation-induced activation of lactate dehydrogenase A (LDHA), an enzyme that catalyses the interconversion of pyruvate and lactate, promotes cancer cell invasion, anoikis resistance and tumour metastasis. We demonstrate that LDHA is phosphorylated at tyrosine 10 by upstream kinases, HER2 and Src. Targeting HER2 or Src attenuated LDH activity as well as invasive potential in head and neck cancer and breast cancer cells. Inhibition of LDH activity by small hairpin ribonucleic acid or expression of phospho-deficient LDHA Y10F sensitized the cancer cells to anoikis induction and resulted in attenuated cell invasion and elevated reactive oxygen species, whereas such phenotypes were reversed by its product lactate or antioxidant N-acetylcysteine, suggesting that Y10 phosphorylation-mediated LDHA activity promotes cancer cell invasion and anoikis resistance through redox homeostasis. In addition, LDHA knockdown or LDHA Y10F rescue expression in human cancer cells resulted in decreased tumour metastasis in xenograft mice. Furthermore, LDHA phosphorylation at Y10 positively correlated with progression of metastatic breast cancer in clinical patient tumour samples. Our findings demonstrate that LDHA phosphorylation and activation provide pro-invasive, anti-anoikis and pro-metastatic advantages to cancer cells, suggesting that Y10 phosphorylation of LDHA may represent a promising therapeutic target and a prognostic marker for metastatic human cancers.
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Affiliation(s)
- L Jin
- Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - J Chun
- Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - C Pan
- Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - GN Alesi
- Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - D Li
- Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - KR Magliocca
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Y Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | - ZG Chen
- Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - DM Shin
- Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - FR Khuri
- Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - J Fan
- Winship Cancer Institute, Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA, USA
| | - S Kang
- Winship Cancer Institute, Department of Hematology/Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA
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Liu Y, Murray-Stewart T, Casero RA, Kagiampakis I, Jin L, Zhang J, Wang H, Che Q, Tong H, Ke J, Jiang F, Wang F, Wan X. Targeting hexokinase 2 inhibition promotes radiosensitization in HPV16 E7-induced cervical cancer and suppresses tumor growth. Int J Oncol 2017; 50:2011-2023. [PMID: 28498475 PMCID: PMC5435328 DOI: 10.3892/ijo.2017.3979] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 04/13/2017] [Indexed: 12/21/2022] Open
Abstract
In order to improve the sensitivity of cervical cancer cells to irradiation therapy, we targeted hexokinase 2 (HK2), the first rate-limiting enzyme of glycolysis, and explore its role in cervical cancer cells. We suppressed HK2 expression and/or function by shRNA and/or metformin and found HK2 inhibition enhanced cells apoptosis with accelerating expression of cleaved PARP and caspase-3. HK2 inhibition also induced much inferior proliferation of cervical cancer cells both in vitro and in vivo with diminishing expression of mTOR, MIB and MGMT. Moreover, HK2 inhibition altered the metabolic profile of cervical cancer cells to one less dependent on glycolysis with a reinforcement of mitochondrial function and an ablation of lactification ability. Importantly, cervical cancer cells contained HK2 inhibition displayed more sensitivity to irradiation. Further results indicated that HPV16 E7 oncoprotein altered the glucose homeostasis of cervical cancer cells into glycolysis by coordinately promoting HK2 expression and its downregulation of glycolysis. Taken together, our findings supported a mechanism whereby targeting HK2 inhibition contributed to suppress HPV16 E7-induced tumor glycolysis metabolism phenotype, inhibiting tumor growth, and induced apoptosis, blocking the cancer cell energy sources and ultimately enhanced the sensitivity of HPV(+) cervical cancer cells to irradiation therapy.
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Affiliation(s)
- Yuan Liu
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Tracy Murray-Stewart
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Robert A Casero
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ioannis Kagiampakis
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lihua Jin
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Jiawen Zhang
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital, Shanghai Tongji University, Shanghai, P.R. China
| | - Huihui Wang
- Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital Affiliated with Shanghai Jiao Tong University, Shanghai, P.R. China
| | - Qi Che
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Huan Tong
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Jieqi Ke
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Feizhou Jiang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Fangyuan Wang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Xiaoping Wan
- Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, P.R. China
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Hirani A, Grover A, Lee YW, Pathak Y, Sutariya V. Nanotechnology for Omics-Based Ocular Drug Delivery. Oncology 2017. [DOI: 10.4018/978-1-5225-0549-5.ch013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Millions of people suffer from ocular diseases that impair vision and can lead to blindness. Advances in genomics and proteomics have revealed a number of different molecular markers specific for different ocular diseases, thereby optimizing the processes of drug development and discovery. Nanotechnology can increase the throughput of data obtained in omics-based studies and allows for more sensitive diagnostic techniques as more efficient drug delivery systems. Biocompatible and biodegradable nanomaterials developed through omics-based research are able to target reported molecular markers for different ocular diseases and offer novel alternatives to conventional drug therapy. In this chapter, the authors review the pathophysiology, current genomic and proteomic information, and current nanomaterial-based therapies of four ocular diseases: glaucoma, uveal melanoma, age-related macular degeneration, and diabetic retinopathy. Omics-based research can be used to elucidate specific genes and proteins and develop novel nanomedicine formulations to prevent, halt, or cure ocular diseases at the transcriptional or translational level.
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Affiliation(s)
- Anjali Hirani
- University of South Florida, USA & Virginia Tech-Wake Forest University, USA
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Huang X, Li X, Xie X, Ye F, Chen B, Song C, Tang H, Xie X. High expressions of LDHA and AMPK as prognostic biomarkers for breast cancer. Breast 2016; 30:39-46. [PMID: 27598996 DOI: 10.1016/j.breast.2016.08.014] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Revised: 08/19/2016] [Accepted: 08/21/2016] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVES The purpose of this study was to investigate the potential correlation between lactate dehydrogenase A (LDHA) and AMP-activated protein kinase (AMPK) and their clinicopathologic significance in breast cancer. MATERIALS AND METHODS Western blot and qRT-PCR were used to detect the expression levels of LDHA and AMPK in eight breast cancer lines and eight breast cancer tissues. In addition, LDHA and AMPK were detected by immunohistochemistry (IHC) using breast cancer tissue microarrays (TMAs) of 112 patients. The association between LDHA and AMPK expression levels was statistically analyzed. So were the prognostic roles and clinicopathologic significances in breast cancer. RESULTS The expression levels of LDHA and AMPK were relatively higher in triple-negative breast cancer (TNBC) cell lines than in non-triple-negative breast cancer (NTNBC) cell lines. LDHA and AMPK were also further up-regulated in TNBC tissues than in NTNBC tissues. Correlation analysis showed a positive correlation between LDHA and AMPK expression levels. Expression of LDHA and AMPK were significantly correlated with TNM stage, distant metastasis, Ki67 status and survival outcomes of patients. Patients with both positive expression of LDHA and AMPK showed shorter overall survival (OS) and disease-free survival (DFS). CONCLUSIONS These findings improve our understanding of the expression pattern of LDHA and AMPK in breast cancer and clarify the role of LDHA and AMPK as promising prognostic biomarkers for breast cancer.
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Affiliation(s)
- Xiaojia Huang
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Xing Li
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Xinhua Xie
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Feng Ye
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Bo Chen
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Cailu Song
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Hailin Tang
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
| | - Xiaoming Xie
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
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50
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Kim SH, Choi SI, Won KY, Lim SJ. Distinctive interrelation of p53 with SCO2, COX, and TIGAR in human gastric cancer. Pathol Res Pract 2016; 212:904-910. [PMID: 27499152 DOI: 10.1016/j.prp.2016.07.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 07/21/2016] [Accepted: 07/26/2016] [Indexed: 12/20/2022]
Abstract
PURPOSE p53, widely known as a tumor-suppressing gene, has recently been reported to regulate glucose metabolism in human cancers through the synthesis of cytochrome c oxidase 2 (SCO2), cytochrome c oxidase complex (COX), and TP53-induced glycolysis and apoptosis regulator (TIGAR). In this study, we investigated the interrelations of the aforementioned proteins, particularly in human gastric cancer, with cancer progression, other clinicopathological parameters, and patient outcomes. MATERIALS AND METHODS One hundred and ten cases of primary gastric cancer occurring from June 2006 to June 2009 were investigated and classified into two groups according to the intensity of immunohistochemical staining for p53, SCO2, COX, and TIGAR. The clinicopathological data were organized and analyzed based on electronic medical records. RESULTS In accordance with previous reports, the expression of p53 showed an inverse correlation with the expression of TIGAR (p=0.032) in gastric cancer cells. However, the expression of SCO2 and COX were not shown to be associated with the regulatory role of p53, unlike TIGAR expression. Nevertheless, a significantly high recurrence rate was found in a patient group with high COX expression (p=0.012). CONCLUSIONS This study demonstrated that a high p53 expression could be associated with the promotion of glycolysis in gastric cancer via the modulation of TIGAR expression. In addition, a high COX expression appeared to be interrelated with poor prognosis of gastric cancer. However, further studies regarding the underlying molecular interactions are required to provide more evidence to propose a novel mechanism that explains our findings in gastric cancer.
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Affiliation(s)
- Sang Hyun Kim
- Department of Surgery, Kyung Hee University School of Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
| | - Sung Il Choi
- Department of Surgery, Kyung Hee University School of Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea.
| | - Kyu Yeoun Won
- Department of Pathology, Kyung Hee University School of Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
| | - Sung-Jig Lim
- Department of Pathology, Kyung Hee University School of Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
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