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Duo R, Wang Y, Ma Q, Wang X, Zhang Y, Shen H. MTX-induced gastrointestinal reactions in RA: Prevotella enrichment, gut dysbiosis, and PI3K/Akt/Ras/AMPK pathways. Clin Rheumatol 2025:10.1007/s10067-025-07406-y. [PMID: 40198451 DOI: 10.1007/s10067-025-07406-y] [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: 11/03/2024] [Revised: 03/12/2025] [Accepted: 03/17/2025] [Indexed: 04/10/2025]
Abstract
OBJECTIVES To investigate the role of gut microbiota in methotrexate (MTX)-induced gastrointestinal reactions (MRGR) in patients with rheumatoid arthritis (RA). METHODS As a prospective, single-center, convenience sampling study, stool samples were obtained from 28 RA patients (male: female = 10:18) at Lanzhou University Second Hospital who were undergoing MTX treatment for analysis of their gut microbiota using 16S rRNA gene sequencing. Clinical disease activity (CDAI) and MRGR were assessed after two months of MTX therapy. All data collection periods exceeded one year. Intestinal germ-free mice, generated through antibiotic treatment, received fecal microbiota transplantation (FMT) from the patients, followed by varying doses of MTX to observe MRGR. Intestinal transcriptomics and markers related to intestinal barrier function were subsequently examined. RESULTS Females (84.6%) and high disease activity (CDAI scores, 39.6 ± 11.2 vs 26.3 ± 9.2) were prone to have MRGR in RA patients. Patients with MRGR (PT-GR) showed lower gut microbial diversity versus non-MRGR (PT-noGR). Prevotella abundance, positively correlated with CDAI and MRGR (p < 0.05), was elevated in PT-GR. Administering 10 mg/kg MTX to mice caused intestinal damage. FMT-GR-MTX mice exhibited weight loss (95.2%), morphological deterioration (86.4%), and reduced tight junction proteins (Claudin-1:72.4%; ZO-1:81.2%). Transcriptomics linked upregulated Gβγ/CREB/Atp4b to PI3K/Akt/Ras pathways and downregulated PFK2/PP2 to AMPK signaling in MRGR. CONCLUSION Our study identified notable gut microbiota alterations in RA patients prone to MRGR, with changes in intestinal gene expression and reduced intestinal barrier function potentially contributing to MRGR. These findings suggest potential strategies to mitigate MRGR in RA patients undergoing MTX treatment. Key Points • The RA-related MRGR is correlated with the intestinal microbiota. • Females, low gut diversity, and Prevotella enrichment are MRGR risks in RA. • Upregulated DEGs in MRGR linked to PI3K/Akt, Ras pathways. • Downregulated DEGs in MRGR focus on the AMPK pathway.
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Affiliation(s)
- Ruixue Duo
- Department of Rheumatology and Immunology, Lanzhou University Second Hospital, 82 Cuiyingmen, Chengguan District, Lanzhou, 730030, Gansu Province, China
- The Second Clinical Medical School, Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Yining Wang
- The Second Clinical Medical School, Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Quanzhi Ma
- The Second Clinical Medical School, Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Xiaoyuan Wang
- Department of Rheumatology and Immunology, Lanzhou University Second Hospital, 82 Cuiyingmen, Chengguan District, Lanzhou, 730030, Gansu Province, China
- The Second Clinical Medical School, Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Yan Zhang
- Department of Rheumatology and Immunology, Lanzhou University Second Hospital, 82 Cuiyingmen, Chengguan District, Lanzhou, 730030, Gansu Province, China
- The Second Clinical Medical School, Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Haili Shen
- Department of Rheumatology and Immunology, Lanzhou University Second Hospital, 82 Cuiyingmen, Chengguan District, Lanzhou, 730030, Gansu Province, China.
- The Second Clinical Medical School, Lanzhou University, Lanzhou, 730030, Gansu, China.
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Aden D, Sureka N, Zaheer S, Chaurasia JK, Zaheer S. Metabolic Reprogramming in Cancer: Implications for Immunosuppressive Microenvironment. Immunology 2025; 174:30-72. [PMID: 39462179 DOI: 10.1111/imm.13871] [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: 05/18/2024] [Revised: 10/07/2024] [Accepted: 10/09/2024] [Indexed: 10/29/2024] Open
Abstract
Cancer is a complex and heterogeneous disease characterised by uncontrolled cell growth and proliferation. One hallmark of cancer cells is their ability to undergo metabolic reprogramming, which allows them to sustain their rapid growth and survival. This metabolic reprogramming creates an immunosuppressive microenvironment that facilitates tumour progression and evasion of the immune system. In this article, we review the mechanisms underlying metabolic reprogramming in cancer cells and discuss how these metabolic alterations contribute to the establishment of an immunosuppressive microenvironment. We also explore potential therapeutic strategies targeting metabolic vulnerabilities in cancer cells to enhance immune-mediated anti-tumour responses. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02044861, NCT03163667, NCT04265534, NCT02071927, NCT02903914, NCT03314935, NCT03361228, NCT03048500, NCT03311308, NCT03800602, NCT04414540, NCT02771626, NCT03994744, NCT03229278, NCT04899921.
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Affiliation(s)
- Durre Aden
- Department of Pathology, Hamdard Institute of Medical Science and Research, New Delhi, India
| | - Niti Sureka
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| | - Samreen Zaheer
- Department of Radiotherapy, Jawaharlal Nehru Medical College, AMU, Aligarh, India
| | | | - Sufian Zaheer
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
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3
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Zhou L, Li J, Wang J, Niu X, Li J, Zhang K. Pathogenic role of PFKFB3 in endothelial inflammatory diseases. Front Mol Biosci 2024; 11:1454456. [PMID: 39318551 PMCID: PMC11419998 DOI: 10.3389/fmolb.2024.1454456] [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: 06/25/2024] [Accepted: 08/30/2024] [Indexed: 09/26/2024] Open
Abstract
The differentiation of vascular endothelial cells and the formation of new blood vessels are inseparable from the energy supply and regulation of metabolism. The budding of blood vessels is a starting point of glycolysis pathway in angiogenesis. Phosphofructokinase-2/fructose 2,6-biophosphatase 3 (PFKFB3), a key rate-limiting enzyme in glycolysis, exhibits strong kinase activity. Inhibition of PFKFB3 can reduce the rate of glycolysis, thereby inhibiting the budding of blood vessels, resulting in inhibition of pathological angiogenesis. In this review, the role of PFKFB3 in the angiogenesis of inflammatory diseases was summarized, and the endothelial inflammatory diseases associated with PFKFB3 were reviewed.
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Affiliation(s)
- Ling Zhou
- ShanXi Key Laboratory of Stem Cells for Immunological Dermatosis, State Key Breeding Laboratory of Stem Cells for Immunological Dermatosis, Taiyuan Central Hospital, Taiyuan, China
| | - Juan Li
- ShanXi Key Laboratory of Stem Cells for Immunological Dermatosis, State Key Breeding Laboratory of Stem Cells for Immunological Dermatosis, Taiyuan Central Hospital, Taiyuan, China
| | - Juanjuan Wang
- ShanXi Key Laboratory of Stem Cells for Immunological Dermatosis, State Key Breeding Laboratory of Stem Cells for Immunological Dermatosis, Taiyuan Central Hospital, Taiyuan, China
| | - Xuping Niu
- ShanXi Key Laboratory of Stem Cells for Immunological Dermatosis, State Key Breeding Laboratory of Stem Cells for Immunological Dermatosis, Taiyuan Central Hospital, Taiyuan, China
| | - Junqin Li
- ShanXi Key Laboratory of Stem Cells for Immunological Dermatosis, State Key Breeding Laboratory of Stem Cells for Immunological Dermatosis, Taiyuan Central Hospital, Taiyuan, China
| | - Kaiming Zhang
- ShanXi Key Laboratory of Stem Cells for Immunological Dermatosis, State Key Breeding Laboratory of Stem Cells for Immunological Dermatosis, Taiyuan Central Hospital, Taiyuan, China
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4
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Masoudi M, Moti D, Masoudi R, Auwal A, Hossain MM, Pronoy TUH, Rashel KM, Gopalan V, Islam F. Metabolic adaptations in cancer stem cells: A key to therapy resistance. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167164. [PMID: 38599259 DOI: 10.1016/j.bbadis.2024.167164] [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: 09/29/2023] [Revised: 03/31/2024] [Accepted: 04/03/2024] [Indexed: 04/12/2024]
Abstract
Cancer stem cells (CSCs) are a subset of tumor cells that can initiate and sustain tumor growth and cause recurrence and metastasis. CSCs are particularly resistant to conventional therapies compared to their counterparts, owing greatly to their intrinsic metabolic plasticity. Metabolic plasticity allows CSCs to switch between different energy production and usage pathways based on environmental and extrinsic factors, including conditions imposed by conventional cancer therapies. To cope with nutrient deprivation and therapeutic stress, CSCs can transpose between glycolysis and oxidative phosphorylation (OXPHOS) metabolism. The mechanism behind the metabolic pathway switch in CSCs is not fully understood, however, some evidence suggests that the tumor microenvironment (TME) may play an influential role mediated by its release of signals, such as Wnt/β-catenin and Notch pathways, as well as a background of hypoxia. Exploring the factors that promote metabolic plasticity in CSCs offers the possibility of eventually developing therapies that may more effectively eliminate the crucial tumor cell subtype and alter the disease course substantially.
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Affiliation(s)
- Matthew Masoudi
- School of Medicine and Dentistry, Griffith University, Gold Coast 4222, Australia
| | - Dilpreet Moti
- School of Medicine and Dentistry, Griffith University, Gold Coast 4222, Australia
| | - Raha Masoudi
- Faculty of Science, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Abdul Auwal
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - M Matakabbir Hossain
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Tasfik Ul Haque Pronoy
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Khan Mohammad Rashel
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh
| | - Vinod Gopalan
- School of Medicine and Dentistry, Griffith University, Gold Coast 4222, Australia
| | - Farhadul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi 6205, Bangladesh.
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Han G, Bai X, Li F, Huang L, Hao Y, Li W, Bu P, Zhang H, Liu X, Xie J. Long non-coding RNA HANR modulates the glucose metabolism of triple negative breast cancer via stabilizing hexokinase 2. Heliyon 2024; 10:e23827. [PMID: 38192790 PMCID: PMC10772629 DOI: 10.1016/j.heliyon.2023.e23827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 12/05/2023] [Accepted: 12/13/2023] [Indexed: 01/10/2024] Open
Abstract
Increasing evidence has demonstrated the oncogenic roles of long non-coding RNA (lncRNA) hepatocellular carcinoma (HCC)-associated long non-coding RNA (HANR) in the development of HCC and lung cancer; however, the involvement of HANR in triple-negative breast cancer (TNBC) remains largely unknown. Our results demonstrated the significant overexpression of HANR in TNBC tissues and cells. Higher HANR levels significantly correlated with the poorer phenotypes in patients with TNBC. HANR down-regulation inhibited the proliferation and cell cycle progression and increased the apoptosis of TNBC cells. Mechanistically, immunoprecipitation-mass spectrometry revealed hexokinase II (HK2) as a direct binding target of HANR. HANR binds to and stabilizes HK2 through the proteasomal pathway. Consistent with the important role of HK2 in cancer cells, HANR depletion represses the glucose absorbance and lactate secretion, thus reprogramming the metabolism of TNBC cells. An in vivo xenograft model also demonstrated that HANR promoted tumor growth and aerobic glycolysis. This study reveals the role of HANR in modulating the glycolysis in TNBC cells by regulating HK2 stability, suggesting that HANR is a potential drug target for TNBC.
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Affiliation(s)
- Guohui Han
- Department of Breast Surgery, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiangdong Bai
- Department of Breast Surgery, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Feng Li
- Department of Biochemistry and Molecular Biology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Li Huang
- Department of Breast Surgery, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yating Hao
- Department of Breast Surgery, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Weina Li
- Department of radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Peng Bu
- Department of Pathology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Huanhu Zhang
- Gastroenterology Department, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xinxin Liu
- Department of Breast Surgery, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jun Xie
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, 030001, China
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Altunok TH, Muchut RJ, Iglesias AA, Yalcin A. Transforming growth factor β1 upregulates 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase-4 expression in A549 and MCF-10A cells. Cell Biochem Funct 2023; 41:1220-1229. [PMID: 37707291 DOI: 10.1002/cbf.3856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/17/2023] [Accepted: 09/04/2023] [Indexed: 09/15/2023]
Abstract
Transforming growth factor β1 (TGFβ1) induces a cellular process known as epithelial-mesenchymal transition (EMT) associated with metabolic reprogramming, including enhanced glycolysis. Given the involvement of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFKFB) enzymes in glycolysis, we aimed to investigate whether TGFβ1 regulates expressions of PFKFB genes and if PFKFBs are required for TGFβ1-driven phenotypes. A549 and MCF-10A cell lines were used as TGFβ1-driven EMT models. Messenger RNA expressions of PFKFB and EMT genes were determined by real-time quantitative polymerase chain reaction. A small interfering RNA approach was used to deplete PFKFB4 expression. A Matrigel invasion assay was conducted to assess the effect of PFKFB4 silencing on the TGFβ1-enhanced invasion of A549 cells. F2,6BP levels were analyzed using an enzyme-coupled assay. Glucose and lactate concentrations were determined using colorimetric assays. TGFβ1 robustly induced expression of the fourth isoform of PFKFBs, PFKFB4, in both cell lines. PFKFB4 depletion partially inhibits mesenchymal transdifferentiation caused by TGFβ1 in A549 cells, as assessed by microscopy. Inductions of Snail in MCF-10A cells and Fibronectin in A549 cells and repressions of E-cadherin in both cell lines by TGFβ1 are attenuated by PFKFB4 silencing. PFKFB4 silencing reduces F2,6BP and glycolytic activity, although TGFβ1 alone does not affect these parameters. Finally, PFKFB4 depletion suppresses the TGFβ1-driven invasion of A549 cells through Matrigel. Presented data suggest that TGFβ1 induces the expression of PFKFB4 in A549 and MCF-10 cells, and PFKFB4 may be required for TGFβ1-driven phenotypes such as EMT and invasion in these models.
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Affiliation(s)
- Tugba H Altunok
- Department of Biochemistry, School of Veterinary Medicine, Bursa Uludag University, Bursa, Turkey
| | - Robertino J Muchut
- Department of Molecular Enzymology, Coastal Agrobiotechnology Institute, National University of Litoral, Santa Fe, Argentina
| | - Alberto A Iglesias
- Department of Molecular Enzymology, Coastal Agrobiotechnology Institute, National University of Litoral, Santa Fe, Argentina
| | - Abdullah Yalcin
- Department of Biochemistry, School of Veterinary Medicine, Bursa Uludag University, Bursa, Turkey
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Icard P, Simula L, Zahn G, Alifano M, Mycielska ME. The dual role of citrate in cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188987. [PMID: 37717858 DOI: 10.1016/j.bbcan.2023.188987] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/04/2023] [Accepted: 09/07/2023] [Indexed: 09/19/2023]
Abstract
Citrate is a key metabolite of the Krebs cycle that can also be exported in the cytosol, where it performs several functions. In normal cells, citrate sustains protein acetylation, lipid synthesis, gluconeogenesis, insulin secretion, bone tissues formation, spermatozoid mobility, and immune response. Dysregulation of citrate metabolism is implicated in several pathologies, including cancer. Here we discuss how cancer cells use citrate to sustain their proliferation, survival, and metastatic progression. Also, we propose two paradoxically opposite strategies to reduce tumour growth by targeting citrate metabolism in preclinical models. In the first strategy, we propose to administer in the tumor microenvironment a high amount of citrate, which can then act as a glycolysis inhibitor and apoptosis inducer, whereas the other strategy targets citrate transporters to starve cancer cells from citrate. These strategies, effective in several preclinical in vitro and in vivo cancer models, could be exploited in clinics, particularly to increase sensibility to current anti-cancer agents.
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Affiliation(s)
- Philippe Icard
- Normandie Univ, UNICAEN, INSERM U1086 Interdisciplinary Research Unit for Cancer Prevention and Treatment, Caen, France; Service of Thoracic Surgery, Cochin Hospital, AP-, HP, 75014, Paris, France.
| | - Luca Simula
- Cochin Institute, INSERM U1016, CNRS UMR8104, University of Paris-Cité, Paris 75014, France
| | | | - Marco Alifano
- Service of Thoracic Surgery, Cochin Hospital, AP-, HP, 75014, Paris, France; INSERM U1138, Integrative Cancer Immunology, University of Paris, 75006 Paris, France
| | - Maria E Mycielska
- Department of Structural Biology, Institute of Biophysics and Physical Biochemistry, University of Regensburg, 93053 Regensburg, Germany
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GÜZEL S, YALÇIN A, GÜRPINAR Y, GÜLER S. Expression of Pfkfb isoenzymes during in vitro differentiation of mouse embryonic stem cells into insulin-producing cells. Turk J Med Sci 2023; 53:1565-1573. [PMID: 38813509 PMCID: PMC10760535 DOI: 10.55730/1300-0144.5725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 12/12/2023] [Accepted: 08/11/2023] [Indexed: 05/31/2024] Open
Abstract
Background/aim Type 1 diabetes mellitus (T1DM) is caused by the autoimmune-mediated destruction of insulin-producing cells (IPCs) and still has no effective cure. Better understanding of the molecular mechanisms involved in the differentiation of embryonic stem cells (ESCs) into IPCs may help us improve the therapeutic strategies for treating T1DM. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (Pfkfb1-4) are key regulators of glucose metabolism. Although Pfkfb3 has been shown to be required for the growth of early differentiated mouse ESCs (mESCs), more studies are needed to further assess the roles of Pfkfb isoenzymes in embryonic development and differentiation, particularly into specific cell types. In this study, we aimed to elucidate the changes in the expression of Pfkfb isoenzymes on the differentiation of mESCs into IPCs. Materials and methods A 3-step protocol was used to differentiate R1 and J1 mESCs into IPCs. The changes in the gene expression of MafA, MafB, Ins2, and Nkx6.1 (IPC specific markers) and Pfkfb1-4 were analyzed using real-time quantitative polymerase chain reaction (qPCR). Insulin expression and secretion were determined by immunofluorescence (IF) staining and the enzyme linked immunosorbent assay (ELISA), respectively. Results Upon differentiation, the IPC specific markers in differentiated cells were upregulated. Continued differentiation was confirmed by the development of insulin-positive islet-like clusters that secreted insulin in response to glucose uptake. Expressions of the Pfkfb2 and Pfkfb3 isoenzymes were markedly increased in various stages of differentiation. Conclusion These findings suggest that Pfkfb2 and Pfkfb3 may impact the differentiation of mESCs into IPCs and the regulation of the insulin response to glucose levels. This study also lays a foundation for researchers to further probe the roles of Pfkfb isoenzymes on the differentiation of mESCs into IPCs and may open new avenues for regenerative medicine.
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Affiliation(s)
- Saime GÜZEL
- Department of Biochemistry, Faculty of Veterinary Medicine, Bursa Uludağ University, Bursa,
Turkiye
| | - Abdullah YALÇIN
- Department of Biochemistry, Faculty of Veterinary Medicine, Bursa Uludağ University, Bursa,
Turkiye
| | - Yunus GÜRPINAR
- Research Center for Translational Medicine, Koç University, İstanbul,
Turkiye
| | - Sabire GÜLER
- Department of Histology & Embryology, Faculty of Veterinary Medicine, Bursa Uludağ University, Bursa,
Turkiye
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Niu N, Ye J, Hu Z, Zhang J, Wang Y. Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis. Int J Mol Sci 2023; 24:ijms24087076. [PMID: 37108242 PMCID: PMC10139088 DOI: 10.3390/ijms24087076] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/23/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
One important feature of tumour development is the regulatory role of metabolic plasticity in maintaining the balance of mitochondrial oxidative phosphorylation and glycolysis in cancer cells. In recent years, the transition and/or function of metabolic phenotypes between mitochondrial oxidative phosphorylation and glycolysis in tumour cells have been extensively studied. In this review, we aimed to elucidate the characteristics of metabolic plasticity (emphasizing their effects, such as immune escape, angiogenesis migration, invasiveness, heterogeneity, adhesion, and phenotypic properties of cancers, among others) on tumour progression, including the initiation and progression phases. Thus, this article provides an overall understanding of the influence of abnormal metabolic remodeling on malignant proliferation and pathophysiological changes in carcinoma.
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Affiliation(s)
- Nan Niu
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
- College of Physics and Optoelectronic Engineering, Canghai Campus of Shenzhen University, Shenzhen 518060, China
| | - Jinfeng Ye
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
| | - Zhangli Hu
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
| | - Junbin Zhang
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
| | - Yun Wang
- Shenzhen Engineering Labortaory for Marine Algal Biotechnology, Longhua Innovation Institute for Biotechnology, College of Life Sciences and Oceanography, Lihu Campus of Shenzhen University, Shenzhen 518055, China
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10
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Targeting mitochondrial impairment for the treatment of cardiovascular diseases: From hypertension to ischemia-reperfusion injury, searching for new pharmacological targets. Biochem Pharmacol 2023; 208:115405. [PMID: 36603686 DOI: 10.1016/j.bcp.2022.115405] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/26/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023]
Abstract
Mitochondria and mitochondrial proteins represent a group of promising pharmacological target candidates in the search of new molecular targets and drugs to counteract the onset of hypertension and more in general cardiovascular diseases (CVDs). Indeed, several mitochondrial pathways result impaired in CVDs, showing ATP depletion and ROS production as common traits of cardiac tissue degeneration. Thus, targeting mitochondrial dysfunction in cardiomyocytes can represent a successful strategy to prevent heart failure. In this context, the identification of new pharmacological targets among mitochondrial proteins paves the way for the design of new selective drugs. Thanks to the advances in omics approaches, to a greater availability of mitochondrial crystallized protein structures and to the development of new computational approaches for protein 3D-modelling and drug design, it is now possible to investigate in detail impaired mitochondrial pathways in CVDs. Furthermore, it is possible to design new powerful drugs able to hit the selected pharmacological targets in a highly selective way to rescue mitochondrial dysfunction and prevent cardiac tissue degeneration. The role of mitochondrial dysfunction in the onset of CVDs appears increasingly evident, as reflected by the impairment of proteins involved in lipid peroxidation, mitochondrial dynamics, respiratory chain complexes, and membrane polarization maintenance in CVD patients. Conversely, little is known about proteins responsible for the cross-talk between mitochondria and cytoplasm in cardiomyocytes. Mitochondrial transporters of the SLC25A family, in particular, are responsible for the translocation of nucleotides (e.g., ATP), amino acids (e.g., aspartate, glutamate, ornithine), organic acids (e.g. malate and 2-oxoglutarate), and other cofactors (e.g., inorganic phosphate, NAD+, FAD, carnitine, CoA derivatives) between the mitochondrial and cytosolic compartments. Thus, mitochondrial transporters play a key role in the mitochondria-cytosol cross-talk by leading metabolic pathways such as the malate/aspartate shuttle, the carnitine shuttle, the ATP export from mitochondria, and the regulation of permeability transition pore opening. Since all these pathways are crucial for maintaining healthy cardiomyocytes, mitochondrial carriers emerge as an interesting class of new possible pharmacological targets for CVD treatments.
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11
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Dong S, Li W, Li X, Wang Z, Chen Z, Shi H, He R, Chen C, Zhou W. Glucose metabolism and tumour microenvironment in pancreatic cancer: A key link in cancer progression. Front Immunol 2022; 13:1038650. [PMID: 36578477 PMCID: PMC9792100 DOI: 10.3389/fimmu.2022.1038650] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
Early and accurate diagnosis and treatment of pancreatic cancer (PC) remain challenging endeavors globally. Late diagnosis lag, high invasiveness, chemical resistance, and poor prognosis are unresolved issues of PC. The concept of metabolic reprogramming is a hallmark of cancer cells. Increasing evidence shows that PC cells alter metabolic processes such as glucose, amino acids, and lipids metabolism and require continuous nutrition for survival, proliferation, and invasion. Glucose metabolism, in particular, regulates the tumour microenvironment (TME). Furthermore, the link between glucose metabolism and TME also plays an important role in the targeted therapy, chemoresistance, radiotherapy ineffectiveness, and immunosuppression of PC. Altered metabolism with the TME has emerged as a key mechanism regulating PC progression. This review shed light on the relationship between TME, glucose metabolism, and various aspects of PC. The findings of this study provide a new direction in the development of PC therapy targeting the metabolism of cancer cells.
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Affiliation(s)
- Shi Dong
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Wancheng Li
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Xin Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Zhengfeng Wang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Zhou Chen
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Huaqing Shi
- The Second School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Ru He
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Chen Chen
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Wence Zhou
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China
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12
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Abedi-Gaballu F, Kamal Kazemi E, Salehzadeh SA, Mansoori B, Eslami F, Emami A, Dehghan G, Baradaran B, Mansoori B, Cho WC. Metabolic Pathways in Breast Cancer Reprograming: An Insight to Non-Coding RNAs. Cells 2022; 11:2973. [PMID: 36230935 PMCID: PMC9563138 DOI: 10.3390/cells11192973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/10/2022] [Accepted: 09/19/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer cells reprogram their metabolisms to achieve high energetic requirements and produce precursors that facilitate uncontrolled cell proliferation. Metabolic reprograming involves not only the dysregulation in glucose-metabolizing regulatory enzymes, but also the enzymes engaging in the lipid and amino acid metabolisms. Nevertheless, the underlying regulatory mechanisms of reprograming are not fully understood. Non-coding RNAs (ncRNAs) as functional RNA molecules cannot translate into proteins, but they do play a regulatory role in gene expression. Moreover, ncRNAs have been demonstrated to be implicated in the metabolic modulations in breast cancer (BC) by regulating the metabolic-related enzymes. Here, we will focus on the regulatory involvement of ncRNAs (microRNA, circular RNA and long ncRNA) in BC metabolism, including glucose, lipid and glutamine metabolism. Investigation of this aspect may not only alter the approaches of BC diagnosis and prognosis, but may also open a new avenue in using ncRNA-based therapeutics for BC treatment by targeting different metabolic pathways.
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Affiliation(s)
- Fereydoon Abedi-Gaballu
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Elham Kamal Kazemi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Seyed Ahmad Salehzadeh
- Department of Medicinal Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 175-14115, Iran
| | - Behnaz Mansoori
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 175-14115, Iran
| | - Farhad Eslami
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Ali Emami
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Gholamreza Dehghan
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz 51666-16471, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14731, Iran
| | - Behzad Mansoori
- Cellular and Molecular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China
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13
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Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies. Cancers (Basel) 2022; 14:cancers14194568. [PMID: 36230492 PMCID: PMC9559313 DOI: 10.3390/cancers14194568] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/14/2022] [Accepted: 09/16/2022] [Indexed: 11/24/2022] Open
Abstract
Simple Summary Reprogramming of glucose metabolism is a hallmark of cancer and can be targeted by therapeutic agents. Some metabolism regulators, such as ivosidenib and enasidenib, have been approved for cancer treatment. Currently, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Furthermore, some natural products have shown efficacy in killing tumor cells by regulating glucose metabolism, offering novel therapeutic opportunities in cancer. However, most of them have failed to be translated into clinical applications due to low selectivity, high toxicity, and side effects. Recent studies suggest that combining glucose metabolism modulators with chemotherapeutic drugs, immunotherapeutic drugs, and other conventional anticancer drugs may be a future direction for cancer treatment. Abstract Reprogramming of glucose metabolism provides sufficient energy and raw materials for the proliferation, metastasis, and immune escape of cancer cells, which is enabled by glucose metabolism-related enzymes that are abundantly expressed in a broad range of cancers. Therefore, targeting glucose metabolism enzymes has emerged as a promising strategy for anticancer drug development. Although several glucose metabolism modulators have been approved for cancer treatment in recent years, some limitations exist, such as a short half-life, poor solubility, and numerous adverse effects. With the rapid development of medicinal chemicals, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Additionally, several studies have found that some natural products can suppress cancer progression by regulating glucose metabolism enzymes. In this review, we summarize the mechanisms underlying the reprogramming of glucose metabolism and present enzymes that could serve as therapeutic targets. In addition, we systematically review the existing drugs targeting glucose metabolism enzymes, including small-molecule modulators and natural products. Finally, the opportunities and challenges for glucose metabolism enzyme-targeted anticancer drugs are also discussed. In conclusion, combining glucose metabolism modulators with conventional anticancer drugs may be a promising cancer treatment strategy.
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14
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Yuan H, Liu X, Wang Z, Ren Y, Li Y, Gao C, Jiao T, Cai Y, Yang Y, Zhao S. Alternative splicing signature of alveolar type II epithelial cells of Tibetan pigs under hypoxia-induced. Front Vet Sci 2022; 9:984703. [PMID: 36187824 PMCID: PMC9523697 DOI: 10.3389/fvets.2022.984703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
Alternative splicing (AS) allows the generation of multiple transcript variants from a single gene and affects biological processes by generating protein diversity in organisms. In total, 41,642 AS events corresponding to 9,924 genes were identified, and SE is the most abundant alternatively spliced type. The analysis of functional categories demonstrates that alternatively spliced differentially expressed genes (DEGs) were enriched in the MAPK signaling pathway and hypoxia-inducible factor 1 (HIF-1) signaling pathway. Proteoglycans in cancer between the normoxic (21% O2, TN and LN) and hypoxic (2% O2, TL and LL) groups, such as SLC2A1, HK1, HK2, ENO3, and PFKFB3, have the potential to rapidly proliferate alveolar type II epithelial (ATII) cells by increasing the intracellular levels of glucose and quickly divert to anabolic pathways by glycolysis intermediates under hypoxia. ACADL, EHHADH, and CPT1A undergo one or two AS types with different frequencies in ATII cells between TN and TL groups (excluding alternatively spliced DEGs shared between normoxic and hypoxic groups), and a constant supply of lipids might be obtained either from the circulation or de novo synthesis for better growth of ATII cells under hypoxia condition. MCM7 and MCM3 undergo different AS types between LN and LL groups (excluding alternatively spliced DEGs shared between normoxic and hypoxic groups), which may bind to the amino-terminal PER-SIM-ARNT domain and the carboxyl terminus of HIF-1α to maintain their stability. Overall, AS and expression levels of candidate mRNAs between Tibetan pigs and Landrace pigs revealed by RNA-seq suggest their potential involvement in the ATII cells grown under hypoxia conditions.
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Affiliation(s)
- Haonan Yuan
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Xuanbo Liu
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Zhengwen Wang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Yue Ren
- Academy of Agriculture and Animal Husbandry Sciences, Institute of Animal Husbandry and Veterinary Medicine, Lhasa, China
| | - Yongqing Li
- Xinjiang Academy of Animal Sciences, Xinjiang, China
| | - Caixia Gao
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Ting Jiao
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
- College of Grassland Science, Gansu Agricultural University, Lanzhou, China
| | - Yuan Cai
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
| | - Yanan Yang
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
- *Correspondence: Yanan Yang
| | - Shengguo Zhao
- College of Animal Science and Technology, Gansu Agricultural University, Lanzhou, China
- Shengguo Zhao
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15
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Zara V, Assalve G, Ferramosca A. Multiple roles played by the mitochondrial citrate carrier in cellular metabolism and physiology. Cell Mol Life Sci 2022; 79:428. [PMID: 35842872 PMCID: PMC9288958 DOI: 10.1007/s00018-022-04466-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 06/17/2022] [Accepted: 07/03/2022] [Indexed: 11/18/2022]
Abstract
The citrate carrier (CIC) is an integral protein of the inner mitochondrial membrane which catalyzes the efflux of mitochondrial citrate (or other tricarboxylates) in exchange with a cytosolic anion represented by a tricarboxylate or a dicarboxylate or phosphoenolpyruvate. In this way, the CIC provides the cytosol with citrate which is involved in many metabolic reactions. Several studies have been carried out over the years on the structure, function and regulation of this metabolite carrier protein both in mammals and in many other organisms. A lot of data on the characteristics of this protein have therefore accumulated over time thereby leading to a complex framework of metabolic and physiological implications connected to the CIC function. In this review, we critically analyze these data starting from the multiple roles played by the mitochondrial CIC in many cellular processes and then examining the regulation of its activity in different nutritional and hormonal states. Finally, the metabolic significance of the citrate flux, mediated by the CIC, across distinct subcellular compartments is also discussed.
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Affiliation(s)
- Vincenzo Zara
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100, Lecce, Italy
| | - Graziana Assalve
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100, Lecce, Italy
| | - Alessandra Ferramosca
- Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100, Lecce, Italy.
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16
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Jones BC, Pohlmann PR, Clarke R, Sengupta S. Treatment against glucose-dependent cancers through metabolic PFKFB3 targeting of glycolytic flux. Cancer Metastasis Rev 2022; 41:447-458. [PMID: 35419769 DOI: 10.1007/s10555-022-10027-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 03/16/2022] [Indexed: 12/11/2022]
Abstract
Reprogrammed metabolism and high energy demand are well-established properties of cancer cells that enable tumor growth. Glycolysis is a primary metabolic pathway that supplies this increased energy demand, leading to a high rate of glycolytic flux and a greater dependence on glucose in tumor cells. Finding safe and effective means to control glycolytic flux and curb cancer cell proliferation has gained increasing interest in recent years. A critical step in glycolysis is controlled by the enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which converts fructose 6-phosphate (F6P) to fructose 2,6-bisphosphate (F2,6BP). F2,6BP allosterically activates the rate-limiting step of glycolysis catalyzed by PFK1 enzyme. PFKFB3 is often overexpressed in many human cancers including pancreatic, colon, prostate, and breast cancer. Hence, PFKFB3 has gained increased interest as a compelling therapeutic target. In this review, we summarize and discuss the current knowledge of PFKFB3 functions, its role in cellular pathways and cancer development, its transcriptional and post-translational activity regulation, and the multiple pharmacologic inhibitors that have been used to block PFKFB3 activity in cancer cells. While much remains to be learned, PFKFB3 continues to hold great promise as an important therapeutic target either as a single agent or in combination with current interventions for breast and other cancers.
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Affiliation(s)
- Brandon C Jones
- Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, 3970 Reservoir Rd NW, Washington, DC, 20057, USA
| | - Paula R Pohlmann
- Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1354, Houston, TX, 77030, USA
| | - Robert Clarke
- The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN, 55912, USA
| | - Surojeet Sengupta
- The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN, 55912, USA.
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17
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Xie S, Pan J, Xu J, Zhu W, Qin L. The critical function of metabolic reprogramming in cancer metastasis. AGING AND CANCER 2022; 3:20-43. [DOI: 10.1002/aac2.12044] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 12/31/2021] [Indexed: 01/03/2025]
Abstract
AbstractCancer metastasis is the leading cause of cancer‐related death. It is a complex, inefficient, and multistep process related to poor prognosis and high mortality of patients. Increasing evidence has shown that metabolic programming is a recognized hallmarker of cancer, plays a critical role in cancer metastasis. Metabolism alterations of glucose, lipid, and amino acid provide cancer cells with energy and substances for biosynthesis, maintain biofunctions and significantly affect proliferation, invasion, and metastasis of cancer cells. Tumor microenvironment (TME) is a complex system formed by varieties of cellular and noncellular elements. Nontumor cells in TME also undergo metabolic reprogramming or respond to metabolites to promote migration and invasion of cancer cells. A comprehensive understanding of the regulatory mechanism in metastasis from the metabolic reprogramming aspect is required to develop new therapeutic strategies combatting cancer metastasis. This review illustrates the metabolic reprogramming and interaction of cancer cells and nontumor cells in the TME, and the development of treatment strategies targeting metabolism alterations.
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Affiliation(s)
- Sun‐Zhe Xie
- Department of General Surgery Huashan Hospital, Fudan University Shanghai China
- Cancer Metastasis Institute Fudan University Shanghai China
| | - Jun‐Jie Pan
- Department of General Surgery Huashan Hospital, Fudan University Shanghai China
- Cancer Metastasis Institute Fudan University Shanghai China
| | - Jian‐Feng Xu
- Department of General Surgery Huashan Hospital, Fudan University Shanghai China
- Cancer Metastasis Institute Fudan University Shanghai China
| | - Wen‐wei Zhu
- Department of General Surgery Huashan Hospital, Fudan University Shanghai China
- Cancer Metastasis Institute Fudan University Shanghai China
| | - Lun‐Xiu Qin
- Department of General Surgery Huashan Hospital, Fudan University Shanghai China
- Cancer Metastasis Institute Fudan University Shanghai China
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18
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Zhang X, Wu Q, Zheng W, Liu C, Huang L, Zuo X, Xiao W, Han X, Ye H, Wang W, Zhu Y, Yang L. Exogenous Linoleic Acid Intervention Alters Hepatic Glucose Metabolism in an Avian Embryo Model. Front Physiol 2022; 13:844148. [PMID: 35264980 PMCID: PMC8899105 DOI: 10.3389/fphys.2022.844148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 01/31/2022] [Indexed: 11/28/2022] Open
Abstract
In the present study, developmental changes of gluconeogenesis and glycolysis in an avian model were measured, and then the intervention effects of in ovo feeding (IOF) linoleic acid (LA) on hepatic glucose metabolism were evaluated. In Experiment 1, thirty fertilized eggs were sampled on embryonic days (E) of 16, 19, 22, 25, 28, 31, and thirty newly-hatched ducklings at hatch (E34 and E35). In Experiment 2, a total of 120 fertilized eggs (60 eggs for each group) were injected into the yolk sac with PBS as the control group and LA as the IOF LA group on E25. Twelve eggs were selected for sample collection on E28 and E31. Serum contents of glucose, pyruvate, and lactate increased ( p < 0.05) linearly or quadratically from E16 to hatch, as well as hepatic glycogen and pyruvate contents. Hepatic mRNA expression related to energy homeostasis, gluconeogenesis, and glycolysis increased ( p < 0.05) in embryogenesis, and the plateau period was presented on E25–E31. IOF LA decreased ( p < 0.05) serum contents of glucose, triacylglycerol, cholesterol, and hepatic oleic acid, unsaturated fatty acids on E28, as well as the gene expression relative to gluconeogenesis. IOF LA increased ( p < 0.05) pyruvate content in serum and liver, and hepatic gene expression relative to glycolysis on E31. In summary, hepatic gluconeogenesis and glycolysis were enhanced to meet the increasing energy demands of embryonic development during E25 – hatch. Exogenous LA intervention on E25 could inhibit hepatic gluconeogenesis and enhance glycolysis during the later developmental period, disrupting glucose embryonic homeostasis and energy status.
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Affiliation(s)
- Xiufen Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Qilin Wu
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Wenxuan Zheng
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Chuang Liu
- Wen’s Food Group Co., Ltd., Yunfu, China
| | - Liang Huang
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Xin Zuo
- Wen’s Food Group Co., Ltd., Yunfu, China
| | | | | | - Hui Ye
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Wence Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Yongwen Zhu
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
- Yongwen Zhu,
| | - Lin Yang
- Guangdong Provincial Key Laboratory of Animal Nutrition and Regulation, College of Animal Science, South China Agricultural University, Guangzhou, China
- *Correspondence: Lin Yang,
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19
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Chen Y, Li Y. Metabolic reprogramming and immunity in cancer. CANCER IMMUNOLOGY AND IMMUNOTHERAPY 2022:137-196. [DOI: 10.1016/b978-0-12-823397-9.00006-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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20
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Structure, regulation, and biological functions of TIGAR and its role in diseases. Acta Pharmacol Sin 2021; 42:1547-1555. [PMID: 33510458 PMCID: PMC8463536 DOI: 10.1038/s41401-020-00588-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 11/22/2020] [Indexed: 02/02/2023]
Abstract
TIGAR (TP53-induced glycolysis and apoptosis regulator) is the downstream target gene of p53, contains a functional sequence similar to 6-phosphofructose kinase/fructose-2, 6-bisphosphatase (PFKFB) bisphosphatase domain. TIGAR is mainly located in the cytoplasm; in response to stress, TIGAR is translocated to nucleus and organelles, including mitochondria and endoplasmic reticulum to regulate cell function. P53 family members (p53, p63, and p73), some transcription factors (SP1 and CREB), and noncoding miRNAs (miR-144, miR-885-5p, and miR-101) regulate the transcription of TIGAR. TIGAR mainly functions as fructose-2,6-bisphosphatase to hydrolyze fructose-1,6-diphosphate and fructose-2,6-diphosphate to inhibit glycolysis. TIGAR in turn facilitates pentose phosphate pathway flux to produce nicotinamide adenine dinucleotide phosphate (NADPH) and ribose, thereby promoting DNA repair, and reducing intracellular reactive oxygen species. TIGAR thus maintains energy metabolism balance, regulates autophagy and stem cell differentiation, and promotes cell survival. Meanwhile, TIGAR also has a nonenzymatic function and can interact with retinoblastoma protein, protein kinase B, nuclear factor-kappa B, hexokinase 2, and ATP5A1 to mediate cell cycle arrest, inflammatory response, and mitochondrial protection. TIGAR might be a potential target for the prevention and treatment of cardiovascular and neurological diseases, as well as cancers.
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21
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Ozcan SC, Mutlu A, Altunok TH, Gurpinar Y, Sarioglu A, Guler S, Muchut RJ, Iglesias AA, Celikler S, Campbell PM, Yalcin A. Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells. Biochem Biophys Res Commun 2021; 571:118-124. [PMID: 34325126 DOI: 10.1016/j.bbrc.2021.07.070] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 12/18/2022]
Abstract
Activating mutations of the oncogenic KRAS in pancreatic ductal adenocarcinoma (PDAC) are associated with an aberrant metabolic phenotype that may be therapeutically exploited. Increased glutamine utilization via glutaminase-1 (GLS1) is one such feature of the activated KRAS signaling that is essential to cell survival and proliferation; however, metabolic plasticity of PDAC cells allow them to adapt to GLS1 inhibition via various mechanisms including activation of glycolysis, suggesting a requirement for combinatorial anti-metabolic approaches to combat PDAC. We investigated whether targeting the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) in combination with GLS1 can selectively prevent the growth of KRAS-transformed cells. We show that KRAS-transformation of pancreatic duct cells robustly sensitizes them to the dual targeting of GLS1 and PFKFB3. We also report that this sensitivity is preserved in the PDAC cell line PANC-1 which harbors an activating KRAS mutation. We then demonstrate that GLS1 inhibition reduced fructose-2,6-bisphosphate levels, the product of PFKFB3, whereas PFKFB3 inhibition increased glutamine consumption, and these effects were augmented by the co-inhibition of GLS1 and PFKFB3, suggesting a reciprocal regulation between PFKFB3 and GLS1. In conclusion, this study identifies a novel mutant KRAS-induced metabolic vulnerability that may be targeted via combinatorial inhibition of GLS1 and PFKFB3 to suppress PDAC cell growth.
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Affiliation(s)
- Selahattin C Ozcan
- Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, 34450, Turkey
| | - Aydan Mutlu
- Department of General Biology, School of Arts & Science, Bursa Uludag University, Bursa, 16059, Turkey
| | - Tugba H Altunok
- Department of Biochemistry, School of Veterinary Medicine, Bursa Uludag University, Bursa, 16059, Turkey
| | - Yunus Gurpinar
- Department of Biochemistry, School of Veterinary Medicine, Bursa Uludag University, Bursa, 16059, Turkey
| | - Aybike Sarioglu
- Department of Biochemistry, School of Veterinary Medicine, Bursa Uludag University, Bursa, 16059, Turkey
| | - Sabire Guler
- Department of Histology & Embryology, School of Veterinary Medicine, Bursa Uludag University, Bursa, 16059, Turkey
| | - Robertino J Muchut
- Department of Molecular Enzymology, Coastal Agrobiotechnology Institute, National University of the Littoral, Santa Fe, 3000, Argentina
| | - Alberto A Iglesias
- Department of Molecular Enzymology, Coastal Agrobiotechnology Institute, National University of the Littoral, Santa Fe, 3000, Argentina
| | - Serap Celikler
- Department of General Biology, School of Arts & Science, Bursa Uludag University, Bursa, 16059, Turkey
| | - Paul M Campbell
- The Marvin and Concetta Greenberg Pancreatic Cancer Institute, Cancer Signaling & Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Abdullah Yalcin
- Department of Biochemistry, School of Veterinary Medicine, Bursa Uludag University, Bursa, 16059, Turkey.
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22
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Heydasch U, Kessler R, Warnke JP, Eschrich K, Scholz N, Bigl M. Functional diversity of PFKFB3 splice variants in glioblastomas. PLoS One 2021; 16:e0241092. [PMID: 34234350 PMCID: PMC8263283 DOI: 10.1371/journal.pone.0241092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 06/08/2021] [Indexed: 11/19/2022] Open
Abstract
Tumor cells tend to metabolize glucose through aerobic glycolysis instead of oxidative phosphorylation in mitochondria. One of the rate limiting enzymes of glycolysis is 6-phosphofructo-1-kinase, which is allosterically activated by fructose 2,6-bisphosphate which in turn is produced by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2 or PFKFB). Mounting evidence suggests that cancerous tissues overexpress the PFKFB isoenzyme, PFKFB3, being causing enhanced proliferation of cancer cells. Initially, six PFKFB3 splice variants with different C-termini have been documented in humans. More recently, additional splice variants with varying N-termini were discovered the functions of which are to be uncovered. Glioblastoma is one of the deadliest forms of brain tumors. Up to now, the role of PFKFB3 splice variants in the progression and prognosis of glioblastomas is only partially understood. In this study, we first re-categorized the PFKFB3 splice variant repertoire to simplify the denomination. We investigated the impact of increased and decreased levels of PFKFB3-4 (former UBI2K4) and PFKFB3-5 (former variant 5) on the viability and proliferation rate of glioblastoma U87 and HEK-293 cells. The simultaneous knock-down of PFKFB3-4 and PFKFB3-5 led to a decrease in viability and proliferation of U87 and HEK-293 cells as well as a reduction in HEK-293 cell colony formation. Overexpression of PFKFB3-4 but not PFKFB3-5 resulted in increased cell viability and proliferation. This finding contrasts with the common notion that overexpression of PFKFB3 enhances tumor growth, but instead suggests splice variant-specific effects of PFKFB3, apparently with opposing effects on cell behaviour. Strikingly, in line with this result, we found that in human IDH-wildtype glioblastomas, the PFKFB3-4 to PFKFB3-5 ratio was significantly shifted towards PFKFB3-4 when compared to control brain samples. Our findings indicate that the expression level of distinct PFKFB3 splice variants impinges on tumorigenic properties of glioblastomas and that splice pattern may be of important diagnostic value for glioblastoma.
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Affiliation(s)
- Ulli Heydasch
- Division of General Biochemistry, Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Renate Kessler
- Division of General Biochemistry, Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Jan-Peter Warnke
- Department of Neurosurgery, Paracelsus Hospital Zwickau, Zwickau, Germany
| | - Klaus Eschrich
- Division of General Biochemistry, Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Nicole Scholz
- Division of General Biochemistry, Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany
| | - Marina Bigl
- Division of General Biochemistry, Rudolf Schönheimer Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany
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23
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Eniafe J, Jiang S. The functional roles of TCA cycle metabolites in cancer. Oncogene 2021; 40:3351-3363. [PMID: 33864000 DOI: 10.1038/s41388-020-01639-8] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/14/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022]
Abstract
The tricarboxylic acid cycle (TCA cycle) has been known for decades as a hub for generating cellular energy and precursors for biosynthetic pathways. Several cancers harbor mutations that affect the integrity of this cycle, mostly at the levels of isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and fumarate hydratase (FH). This results in dysregulation in the production of TCA cycle metabolites and is probably implicated in cancer initiation. By modulating cellular activities, including metabolism and signaling, TCA cycle intermediates are able to impact the processes of cancer development and progression. In this review, we discuss the functional roles of the TCA cycle intermediates in suppressing or promoting the progression of cancers. A further understanding of TCA metabolites' roles and molecular mechanisms in oncogenesis would prompt developing novel metabolite-based cancer therapy in the future.
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Affiliation(s)
- Joseph Eniafe
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA
| | - Shuai Jiang
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA.
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Maurya VK, DeMayo FJ, Lydon JP. Illuminating the "Black Box" of Progesterone-Dependent Embryo Implantation Using Engineered Mice. Front Cell Dev Biol 2021; 9:640907. [PMID: 33898429 PMCID: PMC8058370 DOI: 10.3389/fcell.2021.640907] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 03/11/2021] [Indexed: 02/04/2023] Open
Abstract
Synchrony between progesterone-driven endometrial receptivity and the arrival of a euploid blastocyst is essential for embryo implantation, a prerequisite event in the establishment of a successful pregnancy. Advancement of embryo implantation within the uterus also requires stromal fibroblasts of the endometrium to transform into epithelioid decidual cells, a progesterone-dependent cellular transformation process termed decidualization. Although progesterone is indispensable for these cellular processes, the molecular underpinnings are not fully understood. Because human studies are restricted, much of our fundamental understanding of progesterone signaling in endometrial periimplantation biology comes from in vitro and in vivo experimental systems. In this review, we focus on the tremendous progress attained with the use of engineered mouse models together with high throughput genome-scale analysis in disclosing key signals, pathways and networks that are required for normal endometrial responses to progesterone during the periimplantation period. Many molecular mediators and modifiers of the progesterone response are implicated in cross talk signaling between epithelial and stromal cells of the endometrium, an intercellular communication system that is critical for the ordered spatiotemporal control of embryo invasion within the maternal compartment. Accordingly, derailment of these signaling systems is causally linked with infertility, early embryo miscarriage and gestational complications that symptomatically manifest later in pregnancy. Such aberrant progesterone molecular responses also contribute to endometrial pathologies such as endometriosis, endometrial hyperplasia and cancer. Therefore, our review makes the case that further identification and functional analysis of key molecular mediators and modifiers of the endometrial response to progesterone will not only provide much-needed molecular insight into the early endometrial cellular changes that promote pregnancy establishment but lend credible hope for the development of more effective mechanism-based molecular diagnostics and precision therapies in the clinical management of female infertility, subfertility and a subset of gynecological morbidities.
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Affiliation(s)
- Vineet K Maurya
- Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, United States
| | - Francesco J DeMayo
- Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Durham, NC, United States
| | - John P Lydon
- Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, United States
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25
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Kotowski K, Rosik J, Machaj F, Supplitt S, Wiczew D, Jabłońska K, Wiechec E, Ghavami S, Dzięgiel P. Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets. Cancers (Basel) 2021; 13:909. [PMID: 33671514 PMCID: PMC7926708 DOI: 10.3390/cancers13040909] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 02/12/2021] [Accepted: 02/14/2021] [Indexed: 12/11/2022] Open
Abstract
Glycolysis is a crucial metabolic process in rapidly proliferating cells such as cancer cells. Phosphofructokinase-1 (PFK-1) is a key rate-limiting enzyme of glycolysis. Its efficiency is allosterically regulated by numerous substances occurring in the cytoplasm. However, the most potent regulator of PFK-1 is fructose-2,6-bisphosphate (F-2,6-BP), the level of which is strongly associated with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase activity (PFK-2/FBPase-2, PFKFB). PFK-2/FBPase-2 is a bifunctional enzyme responsible for F-2,6-BP synthesis and degradation. Four isozymes of PFKFB (PFKFB1, PFKFB2, PFKFB3, and PFKFB4) have been identified. Alterations in the levels of all PFK-2/FBPase-2 isozymes have been reported in different diseases. However, most recent studies have focused on an increased expression of PFKFB3 and PFKFB4 in cancer tissues and their role in carcinogenesis. In this review, we summarize our current knowledge on all PFKFB genes and protein structures, and emphasize important differences between the isoenzymes, which likely affect their kinase/phosphatase activities. The main focus is on the latest reports in this field of cancer research, and in particular the impact of PFKFB3 and PFKFB4 on tumor progression, metastasis, angiogenesis, and autophagy. We also present the most recent achievements in the development of new drugs targeting these isozymes. Finally, we discuss potential combination therapies using PFKFB3 inhibitors, which may represent important future cancer treatment options.
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Affiliation(s)
- Krzysztof Kotowski
- Department of Histology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (K.K.); (K.J.)
| | - Jakub Rosik
- Department of Pathology, Pomeranian Medical University, 71-252 Szczecin, Poland; (J.R.); (F.M.)
| | - Filip Machaj
- Department of Pathology, Pomeranian Medical University, 71-252 Szczecin, Poland; (J.R.); (F.M.)
| | - Stanisław Supplitt
- Department of Genetics, Wroclaw Medical University, 50-368 Wroclaw, Poland;
| | - Daniel Wiczew
- Department of Biochemical Engineering, Wroclaw University of Science and Technology, 50-370 Wroclaw, Poland;
- Laboratoire de physique et chimie théoriques, Université de Lorraine, F-54000 Nancy, France
| | - Karolina Jabłońska
- Department of Histology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (K.K.); (K.J.)
| | - Emilia Wiechec
- Department of Biomedical and Clinical Sciences (BKV), Division of Cell Biology, Linköping University, Region Östergötland, 581 85 Linköping, Sweden;
- Department of Otorhinolaryngology in Linköping, Anesthetics, Operations and Specialty Surgery Center, Region Östergötland, 581 85 Linköping, Sweden
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- Research Institute in Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
| | - Piotr Dzięgiel
- Department of Histology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (K.K.); (K.J.)
- Department of Physiotherapy, Wroclaw University School of Physical Education, 51-612 Wroclaw, Poland
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26
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Zhu X, Chen HH, Gao CY, Zhang XX, Jiang JX, Zhang Y, Fang J, Zhao F, Chen ZG. Energy metabolism in cancer stem cells. World J Stem Cells 2020; 12:448-461. [PMID: 32742562 PMCID: PMC7360992 DOI: 10.4252/wjsc.v12.i6.448] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/09/2020] [Accepted: 05/19/2020] [Indexed: 02/06/2023] Open
Abstract
Normal cells mainly rely on oxidative phosphorylation as an effective energy source in the presence of oxygen. In contrast, most cancer cells use less efficient glycolysis to produce ATP and essential biomolecules. Cancer cells gain the characteristics of metabolic adaptation by reprogramming their metabolic mechanisms to meet the needs of rapid tumor growth. A subset of cancer cells with stem characteristics and the ability to regenerate exist throughout the tumor and are therefore called cancer stem cells (CSCs). New evidence indicates that CSCs have different metabolic phenotypes compared with differentiated cancer cells. CSCs can dynamically transform their metabolic state to favor glycolysis or oxidative metabolism. The mechanism of the metabolic plasticity of CSCs has not been fully elucidated, and existing evidence indicates that the metabolic phenotype of cancer cells is closely related to the tumor microenvironment. Targeting CSC metabolism may provide new and effective methods for the treatment of tumors. In this review, we summarize the metabolic characteristics of cancer cells and CSCs and the mechanisms of the metabolic interplay between the tumor microenvironment and CSCs, and discuss the clinical implications of targeting CSC metabolism.
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Affiliation(s)
- Xuan Zhu
- Department of Radiation Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Hui-Hui Chen
- The Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Chen-Yi Gao
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Xin-Xin Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Jing-Xin Jiang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Yi Zhang
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Jun Fang
- Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Feng Zhao
- Department of Radiation Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Zhi-Gang Chen
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310000, Zhejiang Province, China
- Department of Breast Surgery, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China.
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Wilkie MD, Anaam EA, Lau AS, Rubbi CP, Jones TM, Boyd MT, Vlatković N. TP53 mutations in head and neck cancer cells determine the Warburg phenotypic switch creating metabolic vulnerabilities and therapeutic opportunities for stratified therapies. Cancer Lett 2020; 478:107-121. [PMID: 32113989 PMCID: PMC7133053 DOI: 10.1016/j.canlet.2020.02.032] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 01/08/2020] [Accepted: 02/24/2020] [Indexed: 12/30/2022]
Abstract
Patients with mutated TP53 have been identified as having comparatively poor outcomes compared to those retaining wild-type p53 in many cancers, including squamous cell carcinomas of the head and neck (SCCHN). We have examined the role of p53 in regulation of metabolism in SCCHN cells and find that loss of p53 function determines the Warburg effect in these cells. Moreover, this metabolic adaptation to loss of p53 function creates an Achilles' heel for tumour cells that can be exploited for potential therapeutic benefit. Specifically, cells lacking normal wild-type p53 function, whether through mutation or RNAi-mediated downregulation, display a lack of metabolic flexibility, becoming more dependent on glycolysis and losing the ability to increase energy production from oxidative phosphorylation. Thus, cells that have compromised p53 function can be sensitised to ionizing radiation by pre-treatment with a glycolytic inhibitor. These results demonstrate the deterministic role of p53 in regulating energy metabolism and provide proof of principle evidence for an opportunity for patient stratification based on p53 status that can be exploited therapeutically using current standard of care treatment with ionising radiation.
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Affiliation(s)
- Mark D Wilkie
- Department of Molecular & Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, 200 London Road, Liverpool, L3 9TA, UK; Department of Otorhinolaryngology - Head & Neck Surgery, University Hospital Aintree, Lower Lane, Liverpool, L9 7AL, UK
| | - Emad A Anaam
- Department of Molecular & Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, 200 London Road, Liverpool, L3 9TA, UK
| | - Andrew S Lau
- Department of Molecular & Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, 200 London Road, Liverpool, L3 9TA, UK; Department of Otorhinolaryngology - Head & Neck Surgery, University Hospital Aintree, Lower Lane, Liverpool, L9 7AL, UK
| | - Carlos P Rubbi
- Department of Molecular & Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, 200 London Road, Liverpool, L3 9TA, UK
| | - Terence M Jones
- Department of Molecular & Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, 200 London Road, Liverpool, L3 9TA, UK; Department of Otorhinolaryngology - Head & Neck Surgery, University Hospital Aintree, Lower Lane, Liverpool, L9 7AL, UK
| | - Mark T Boyd
- Department of Molecular & Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, 200 London Road, Liverpool, L3 9TA, UK
| | - Nikolina Vlatković
- Department of Molecular & Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, 200 London Road, Liverpool, L3 9TA, UK.
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28
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Mori K, Miura N, Mostafaei H, Quhal F, Motlagh RS, Lysenko I, Kimura S, Egawa S, Karakiewicz PI, Shariat SF. Prognostic value of preoperative hematologic biomarkers in urothelial carcinoma of the bladder treated with radical cystectomy: a systematic review and meta-analysis. Int J Clin Oncol 2020; 25:1459-1474. [PMID: 32451768 PMCID: PMC7392936 DOI: 10.1007/s10147-020-01690-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Accepted: 04/27/2020] [Indexed: 12/21/2022]
Abstract
This systematic review and meta-analysis aimed to assess the prognostic value of preoperative hematologic biomarkers in patients with urothelial carcinoma of the bladder treated with radical cystectomy. PUBMED, Web of Science, Cochrane Library, and Scopus databases were searched in September 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they compared cancer-specific survival in patients with urothelial carcinoma of the bladder with and without pretreatment laboratoryabnormalities. Formal meta-analyses were performed for this outcome. The systematic review identified 36 studies with 23,632 patients, of these, 32 studies with 22,224 patients were eligible for the meta-analysis. Several preoperative hematologic biomarkers were significantly associated with cancer-specific survival as follows: neutrophil − lymphocyte ratio (pooled hazard ratio [HR]: 1.20, 95% confidence interval [CI]: 1.11–1.29), hemoglobin (pooled HR: 0.87, 95% CI 0.82–0.94), C-reactive protein (pooled HR: 1.44, 95% CI 1.26–1.66), De Ritis ratio (pooled HR: 2.18, 95% CI 1.37–3.48), white blood cell count (pooled HR: 1.05, 95% CI 1.02–1.07), and albumin-globulin ratio (pooled HR: 0.26, 95% CI 0.14–0.48). Several pretreatment laboratory abnormalities in patients with urothelial carcinoma of the bladder were associated with cancer-specific mortality. Therefore, it might be useful to incorporate such hematologic biomarkers into prognostic tools for urothelial carcinoma of the bladder. However, given the study limitations including heterogeneity and retrospective nature of the primary data, the conclusions should be interpreted with caution.
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Affiliation(s)
- Keiichiro Mori
- Department of Urology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Noriyoshi Miura
- Department of Urology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Department of Urology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Hadi Mostafaei
- Department of Urology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fahad Quhal
- Department of Urology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Department of Urology, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Reza Sari Motlagh
- Department of Urology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Ivan Lysenko
- Department of Urology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Shoji Kimura
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Shin Egawa
- Department of Urology, The Jikei University School of Medicine, Tokyo, Japan
| | - Pierre I Karakiewicz
- Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Centre, Montreal, Canada
| | - Shahrokh F Shariat
- Department of Urology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
- Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.
- Department of Urology, Weill Cornell Medical College, New York, NY, USA.
- Department of Urology, University of Texas Southwestern, Dallas, TX, USA.
- Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria.
- Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
- Department of Urology, University of Jordan, Amman, Jordan.
- European Association of Urology Research Foundation, Arnhem, The Netherlands.
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29
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PFKFB2 regulates glycolysis and proliferation in pancreatic cancer cells. Mol Cell Biochem 2020; 470:115-129. [PMID: 32415418 DOI: 10.1007/s11010-020-03751-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 05/08/2020] [Indexed: 12/27/2022]
Abstract
Tumor cells increase glucose metabolism through glycolysis and pentose phosphate pathways to meet the bioenergetic and biosynthetic demands of rapid cell proliferation. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are key regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent activator of glycolysis. Previous studies have reported the co-expression of PFKFB isozymes, as well as the mRNA splice variants of particular PFKFB isozymes, suggesting non-redundant functions. Majority of the evidence demonstrating a requirement for PFKFB activity in increased glycolysis and oncogenic properties in tumor cells comes from studies on PFKFB3 and PFKFB4 isozymes. In this study, we show that the PFKFB2 isozyme is expressed in tumor cell lines of various origin, overexpressed and localizes to the nucleus in pancreatic adenocarcinoma, relative to normal pancreatic tissue. We then demonstrate the differential intracellular localization of two PFKFB2 mRNA splice variants and that, when ectopically expressed, cytoplasmically localized mRNA splice variant causes a greater increase in F2,6BP which coincides with an increased glucose uptake, as compared with the mRNA splice variant localizing to the nucleus. We then show that PFKFB2 expression is required for steady-state F2,6BP levels, glycolytic activity, and proliferation of pancreatic adenocarcinoma cells. In conclusion, this study may provide a rationale for detailed investigation of PFKFB2's requirement for the glycolytic and oncogenic phenotype of pancreatic adenocarcinoma cells.
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30
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Metabolic reprogramming and disease progression in cancer patients. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165721. [PMID: 32057942 DOI: 10.1016/j.bbadis.2020.165721] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/22/2020] [Accepted: 02/09/2020] [Indexed: 12/19/2022]
Abstract
Genomics has contributed to the treatment of a fraction of cancer patients. However, there is a need to profile the proteins that define the phenotype of cancer and its pathogenesis. The reprogramming of metabolism is a major trait of the cancer phenotype with great potential for prognosis and targeted therapy. This review overviews the major changes reported in the steady-state levels of proteins of metabolism in primary carcinomas, paying attention to those enzymes that correlate with patients' survival. The upregulation of enzymes of glycolysis, pentose phosphate pathway, lipogenesis, glutaminolysis and the antioxidant defense is concurrent with the downregulation of mitochondrial proteins involved in oxidative phosphorylation, emphasizing the potential of mitochondrial metabolism as a promising therapeutic target in cancer. We stress that high-throughput quantitative expression profiling of differentially expressed proteins in large cohorts of carcinomas paired with normal tissues will accelerate translation of metabolism to a successful personalized medicine in cancer.
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31
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Luo H, Yu Q, Liu Y, Tang M, Liang M, Zhang D, Xiao TS, Wu L, Tan M, Ruan Y, Bungert J, Lu J. LATS kinase-mediated CTCF phosphorylation and selective loss of genomic binding. SCIENCE ADVANCES 2020; 6:eaaw4651. [PMID: 32128389 PMCID: PMC7030924 DOI: 10.1126/sciadv.aaw4651] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 12/04/2019] [Indexed: 06/10/2023]
Abstract
Chromatin topological organization is instrumental in gene transcription. Gene-enhancer interactions are accommodated in the same CTCF-mediated insulated neighborhoods. However, it remains poorly understood whether and how the 3D genome architecture is dynamically restructured by external signals. Here, we report that LATS kinases phosphorylated CTCF in the zinc finger (ZF) linkers and disabled its DNA-binding activity. Cellular stress induced LATS nuclear translocation and CTCF ZF linker phosphorylation, and altered the landscape of CTCF genomic binding partly by dissociating it selectively from a small subset of its genomic binding sites. These sites were highly enriched for the boundaries of chromatin domains containing LATS signaling target genes. The stress-induced CTCF phosphorylation and locus-specific dissociation from DNA were LATS-dependent. Loss of CTCF binding disrupted local chromatin domains and down-regulated genes located within them. The study suggests that external signals may rapidly modulate the 3D genome by affecting CTCF genomic binding through ZF linker phosphorylation.
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Affiliation(s)
- Huacheng Luo
- Department of Biochemistry and Molecular Biology, UF Health Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Qin Yu
- Department of Biochemistry and Molecular Biology, UF Health Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Yang Liu
- Department of Biochemistry and Molecular Biology, UF Health Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Ming Tang
- Department of Biochemistry and Molecular Biology, UF Health Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Mingwei Liang
- Department of Biochemistry and Molecular Biology, UF Health Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Dingpeng Zhang
- Department of Biochemistry and Molecular Biology, UF Health Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Tsan Sam Xiao
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Lizi Wu
- Department of Molecular Genetics and Microbiology, UF Health Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Ming Tan
- Center for Cell Death and Metabolism, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36688, USA
| | - Yijun Ruan
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA
| | - Jörg Bungert
- Department of Biochemistry and Molecular Biology, UF Health Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Jianrong Lu
- Department of Biochemistry and Molecular Biology, UF Health Cancer Center, College of Medicine, University of Florida, Gainesville, FL 32610, USA
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32
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Abdel-Wahab AF, Mahmoud W, Al-Harizy RM. Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res 2019; 150:104511. [DOI: 10.1016/j.phrs.2019.104511] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 10/19/2019] [Accepted: 10/23/2019] [Indexed: 12/24/2022]
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Huang L, Wang C, Xu H, Peng G. Targeting citrate as a novel therapeutic strategy in cancer treatment. Biochim Biophys Acta Rev Cancer 2019; 1873:188332. [PMID: 31751601 DOI: 10.1016/j.bbcan.2019.188332] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 11/14/2019] [Accepted: 11/15/2019] [Indexed: 01/09/2023]
Abstract
An important feature shared by many cancer cells is drastically altered metabolism that is critical for rapid growth and proliferation. The distinctly reprogrammed metabolism in cancer cells makes it possible to manipulate the levels of metabolites for cancer treatment. Citrate is a key metabolite that bridges many important metabolic pathways. Recent studies indicate that manipulating the level of citrate can impact the behaviors of both cancer and immune cells, resulting in induction of cancer cell apoptosis, boosting immune responses, and enhanced cancer immunotherapy. In this review, we discuss the recent developments in this emerging area of targeting citrate in cancer treatment. Specifically, we summarize the molecular basis of altered citrate metabolism in both tumors and immune cells, explore the seemingly conflicted growth promoting and growth inhibiting roles of citrate in various tumors, discuss the use of citrate in the clinic as a novel biomarker for cancer progression and outcomes, and highlight the new development of combining citrate with other therapeutic strategies in cancer therapy. An improved understanding of complex roles of citrate in the suppressive tumor microenvironment should open new avenues for cancer therapy.
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Affiliation(s)
- Lan Huang
- Division of Infectious Diseases, Allergy & Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA; Department of Immunology, Jiangsu University School of Medicine, Zhenjiang 212013, PR China
| | - Cindy Wang
- Division of Infectious Diseases, Allergy & Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA
| | - Huaxi Xu
- Department of Immunology, Jiangsu University School of Medicine, Zhenjiang 212013, PR China
| | - Guangyong Peng
- Division of Infectious Diseases, Allergy & Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA.
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34
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Palermo A, Naciu AM, Tabacco G, Manfrini S, Trimboli P, Vescini F, Falchetti A. Calcium citrate: from biochemistry and physiology to clinical applications. Rev Endocr Metab Disord 2019; 20:353-364. [PMID: 31643038 DOI: 10.1007/s11154-019-09520-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Adequate daily calcium intake should normally be achieved by dietary sources. Since low calcium diets are quite common in subjects that do not reach the recommended intake and particularly those at risk of fractures, calcium supplements may become necessary. Different forms of calcium salts are available, but products containing calcium citrate and calcium carbonate complexes are the most frequently used. Although only limited evidence on the efficacy and long-term safety of calcium citrate is available, these supplements may represent a valuable product for the management of different chronic pathological conditions. The aim of this review was to evaluate the current and potential clinical applications of calcium citrate. In particular, we focused on the use of calcium citrate supplementation in subjects with osteoporosis or in bariatric patients. Other pathological conditions that could benefit calcium citrate supplementation may include achloridria, chronic hypoparathyroidism and hypocitraturic subjects with moderate/high risk of nephrolithiasis. Indeed, citrate salts are widely used in the treatment of nephrolithiasis, since they have shown an inhibitory effect on kidney stone formation and recurrence.
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Affiliation(s)
- Andrea Palermo
- Unit of Endocrinology and Diabetes, Campus Bio-Medico University, Rome, Italy.
| | - Anda Mihaela Naciu
- Unit of Endocrinology and Diabetes, Campus Bio-Medico University, Rome, Italy
| | - Gaia Tabacco
- Unit of Endocrinology and Diabetes, Campus Bio-Medico University, Rome, Italy
| | - Silvia Manfrini
- Unit of Endocrinology and Diabetes, Campus Bio-Medico University, Rome, Italy
| | - Pierpaolo Trimboli
- Department of Nuclear Medicine and Thyroid Centre, Imaging Institute of Southern Switzerland, Lugano, Switzerland
| | - Fabio Vescini
- Endocrinology and Metabolism Unit, University-Hospital S. Maria della Misericordia of Udine, 33100, Udine, Italy
| | - Alberto Falchetti
- Istituto Auxologico Italiano, IRCCS, Unit for Bone Metabolism Diseases and Diabetes & Lab of Endocrine and Metabolic Research, University of Milan, Milan, Italy
- EndOsMet, Villa Donatello Private Hospital, Florence, Italy
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Carvalho TM, Cardoso HJ, Figueira MI, Vaz CV, Socorro S. The peculiarities of cancer cell metabolism: A route to metastasization and a target for therapy. Eur J Med Chem 2019; 171:343-363. [PMID: 30928707 DOI: 10.1016/j.ejmech.2019.03.053] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 03/19/2019] [Accepted: 03/21/2019] [Indexed: 02/06/2023]
Abstract
The last decade has witnessed the peculiarities of metabolic reprogramming in tumour onset and progression, and their relevance in cancer therapy. Also, it has been indicated that the metastatic process may depend on the metabolic rewiring and adaptation of cancer cells to the pressure of tumour microenvironment and limiting nutrient availability. The present review gatherers the existent knowledge on the influence of tumour microenvironment and metabolic routes driving metastasis. A focus will be given to glycolysis, fatty acid metabolism, glutaminolysis, and amino acid handling. In addition, the role of metabolic waste driving metastasization will be explored. Finally, we discuss the status of cancer treatment approaches targeting metabolism. This knowledge revision will highlight the critical metabolic targets in metastasis and the chemicals already used in preclinical studies and clinical trials, providing clues that would be further exploited in medicinal chemistry research.
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Affiliation(s)
- Tiago Ma Carvalho
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Henrique J Cardoso
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Marília I Figueira
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Cátia V Vaz
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Sílvia Socorro
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
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Raben DM, Wolfgang MJ. Energy Metabolism | Phosphofructokinase-2/Fructose Bisphosphatase-2. ENCYCLOPEDIA OF BIOLOGICAL CHEMISTRY III 2019:162-165. [DOI: 10.1016/b978-0-12-819460-7.00606-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Synthesis of amide and sulfonamide substituted N-aryl 6-aminoquinoxalines as PFKFB3 inhibitors with improved physicochemical properties. Bioorg Med Chem Lett 2018; 29:646-653. [PMID: 30626557 DOI: 10.1016/j.bmcl.2018.12.034] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 12/11/2018] [Accepted: 12/14/2018] [Indexed: 12/13/2022]
Abstract
In oncology, the "Warburg effect" describes the elevated production of energy by glycolysis in cancer cells. The ubiquitous and hypoxia-induced 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a noteworthy role in the regulation of glycolysis by producing fructose-2,6-biphosphate (F-2,6-BP), a potent activator of the glycolysis rate-limiting phosphofructokinase PFK-1. Series of amides and sulfonamides derivatives based on a N-aryl 6-aminoquinoxaline scaffold were synthesized and tested for their inhibition of PFKFB3 in vitro in a biochemical assay as well as in HCT116 cells. The carboxamide series displayed satisfactory kinetic solubility and metabolic stability, and within this class, potent lead compounds with low nanomolar activity have been identified with a suitable profile for further in vivo evaluation.
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Boutard N, Białas A, Sabiniarz A, Guzik P, Banaszak K, Biela A, Bień M, Buda A, Bugaj B, Cieluch E, Cierpich A, Dudek Ł, Eggenweiler H, Fogt J, Gaik M, Gondela A, Jakubiec K, Jurzak M, Kitlińska A, Kowalczyk P, Kujawa M, Kwiecińska K, Leś M, Lindemann R, Maciuszek M, Mikulski M, Niedziejko P, Obara A, Pawlik H, Rzymski T, Sieprawska‐Lupa M, Sowińska M, Szeremeta‐Spisak J, Stachowicz A, Tomczyk MM, Wiklik K, Włoszczak Ł, Ziemiańska S, Zarębski A, Brzózka K, Nowak M, Fabritius C. Discovery and Structure–Activity Relationships of
N
‐Aryl 6‐Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors. ChemMedChem 2018; 14:169-181. [DOI: 10.1002/cmdc.201800569] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 10/13/2018] [Indexed: 01/09/2023]
Affiliation(s)
| | | | | | - Paweł Guzik
- Selvita S.A. Bobrzyńskiego 14 30-348 Kraków Poland
| | | | - Artur Biela
- Selvita S.A. Bobrzyńskiego 14 30-348 Kraków Poland
| | - Marcin Bień
- Selvita S.A. Bobrzyńskiego 14 30-348 Kraków Poland
- Current address: Almac Group 20 Seagoe Industrial Estate Craigavon BT63 5QD UK
| | - Anna Buda
- Selvita S.A. Bobrzyńskiego 14 30-348 Kraków Poland
| | | | | | - Anna Cierpich
- Selvita S.A. Bobrzyńskiego 14 30-348 Kraków Poland
- Current address: Grupa Azoty S.A. Kwiatkowskiego 8 33-100 Tarnów Poland
| | - Łukasz Dudek
- Selvita S.A. Bobrzyńskiego 14 30-348 Kraków Poland
| | | | - Joanna Fogt
- Selvita S.A. Bobrzyńskiego 14 30-348 Kraków Poland
| | - Monika Gaik
- Selvita S.A. Bobrzyńskiego 14 30-348 Kraków Poland
- Current address: Max Planck Research Group at the Małopolska Centre of Biotechnology Jagiellonian University Krakow Poland
| | | | | | - Mirek Jurzak
- Discovery Pharmacology, Merck Biopharma Merck KGaA Frankfurter Straße 250 64293 Darmstadt Germany
| | | | | | | | - Katarzyna Kwiecińska
- Selvita S.A. Bobrzyńskiego 14 30-348 Kraków Poland
- Current address: Captor Therapeutics Duńska 11 54-427 Wrocław Poland
| | - Marcin Leś
- Selvita S.A. Bobrzyńskiego 14 30-348 Kraków Poland
| | - Ralph Lindemann
- Translational Innovation Platform Oncology, Merck Biopharma Merck KGaA Frankfurter Straße 250 64293 Darmstadt Germany
| | - Monika Maciuszek
- Selvita S.A. Bobrzyńskiego 14 30-348 Kraków Poland
- Current address: LifeArc Accelerator Building, Open Innovation Campus Stevenage SG1 2FX UK
| | | | | | - Alicja Obara
- Selvita S.A. Bobrzyńskiego 14 30-348 Kraków Poland
| | | | | | | | | | | | | | - Mateusz M. Tomczyk
- Selvita S.A. Bobrzyńskiego 14 30-348 Kraków Poland
- Current address: Katedra Chemii Organicznej Bioorganicznej I Biotechnologii Ul. B. Krzywoustego 4, P., 18/N1 44-100 Gliwice Poland
| | | | - Łukasz Włoszczak
- Selvita S.A. Bobrzyńskiego 14 30-348 Kraków Poland
- Current address: Grupa Adamed Pieńków 149 05-152 Czosnów Poland
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Yi M, Ban Y, Tan Y, Xiong W, Li G, Xiang B. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 and 4: A pair of valves for fine-tuning of glucose metabolism in human cancer. Mol Metab 2018; 20:1-13. [PMID: 30553771 PMCID: PMC6358545 DOI: 10.1016/j.molmet.2018.11.013] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 11/27/2018] [Accepted: 11/30/2018] [Indexed: 12/12/2022] Open
Abstract
Background Cancer cells favor the use of less efficient glycolysis rather than mitochondrial oxidative phosphorylation to metabolize glucose, even in oxygen-rich conditions, a distinct metabolic alteration named the Warburg effect or aerobic glycolysis. In adult cells, bifunctional 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB) family members are responsible for controlling the steady-state cytoplasmic levels of fructose-2,6-bisphosphate, which allosterically activates 6-phosphofructo-1-kinase, the key enzyme catalyzing the rate-limiting reaction of glycolysis. PFKFB3 and PFKFB4 are the two main isoenzymes overexpressed in various human cancers. Scope of review In this review, we summarize recent findings on the glycolytic and extraglycolytic roles of PFKFB3 and PFKFB4 in cancer progression and discuss potential therapies for targeting of PFKFB3 and PFKFB4. Major conclusions PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species. Co-expression of PFKFB3 and PFKFB4 provides sufficient glucose metabolism to satisfy the bioenergetics demand and redox homeostasis requirements of cancer cells. Various reversible post-translational modifications of PFKFB3 enable cancer cells to flexibly adapt glucose metabolism in response to diverse stress conditions. In addition to playing important roles in tumor cell glucose metabolism, PFKFB3 and PFKFB4 are widely involved in multiple biological processes, such as cell cycle regulation, autophagy, and transcriptional regulation in a non-glycolysis-dependent manner.
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Affiliation(s)
- Mei Yi
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, Hunan 410013, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; Department of Dermatology, Xiangya Hospital, The Central South University, Changsha, 410008, Hunan, China
| | - Yuanyuan Ban
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, Hunan 410013, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Yixin Tan
- Department of Dermatology, Second Xiangya Hospital, The Central South University, Hunan Key Laboratory of Medical Epigenetics, Changsha, 410011, Hunan, China
| | - Wei Xiong
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, Hunan 410013, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Guiyuan Li
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, Hunan 410013, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Bo Xiang
- Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, Hunan 410013, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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Bartrons R, Simon-Molas H, Rodríguez-García A, Castaño E, Navarro-Sabaté À, Manzano A, Martinez-Outschoorn UE. Fructose 2,6-Bisphosphate in Cancer Cell Metabolism. Front Oncol 2018; 8:331. [PMID: 30234009 PMCID: PMC6131595 DOI: 10.3389/fonc.2018.00331] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 08/01/2018] [Indexed: 01/28/2023] Open
Abstract
For a long time, pioneers in the field of cancer cell metabolism, such as Otto Warburg, have focused on the idea that tumor cells maintain high glycolytic rates even with adequate oxygen supply, in what is known as aerobic glycolysis or the Warburg effect. Recent studies have reported a more complex situation, where the tumor ecosystem plays a more critical role in cancer progression. Cancer cells display extraordinary plasticity in adapting to changes in their tumor microenvironment, developing strategies to survive and proliferate. The proliferation of cancer cells needs a high rate of energy and metabolic substrates for biosynthesis of biomolecules. These requirements are met by the metabolic reprogramming of cancer cells and others present in the tumor microenvironment, which is essential for tumor survival and spread. Metabolic reprogramming involves a complex interplay between oncogenes, tumor suppressors, growth factors and local factors in the tumor microenvironment. These factors can induce overexpression and increased activity of glycolytic isoenzymes and proteins in stromal and cancer cells which are different from those expressed in normal cells. The fructose-6-phosphate/fructose-1,6-bisphosphate cycle, catalyzed by 6-phosphofructo-1-kinase/fructose 1,6-bisphosphatase (PFK1/FBPase1) isoenzymes, plays a key role in controlling glycolytic rates. PFK1/FBpase1 activities are allosterically regulated by fructose-2,6-bisphosphate, the product of the enzymatic activity of the dual kinase/phosphatase family of enzymes: 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFKFB1-4) and TP53-induced glycolysis and apoptosis regulator (TIGAR), which show increased expression in a significant number of tumor types. In this review, the function of these isoenzymes in the regulation of metabolism, as well as the regulatory factors modulating their expression and activity in the tumor ecosystem are discussed. Targeting these isoenzymes, either directly or by inhibiting their activating factors, could be a promising approach for treating cancers.
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Affiliation(s)
- Ramon Bartrons
- Unitat de Bioquímica, Departament de Ciències Fisiològiques, Universitat de Barcelona, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Catalunya, Spain
| | - Helga Simon-Molas
- Unitat de Bioquímica, Departament de Ciències Fisiològiques, Universitat de Barcelona, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Catalunya, Spain
| | - Ana Rodríguez-García
- Unitat de Bioquímica, Departament de Ciències Fisiològiques, Universitat de Barcelona, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Catalunya, Spain
| | - Esther Castaño
- Centres Científics i Tecnològics, Universitat de Barcelona, Catalunya, Spain
| | - Àurea Navarro-Sabaté
- Unitat de Bioquímica, Departament de Ciències Fisiològiques, Universitat de Barcelona, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Catalunya, Spain
| | - Anna Manzano
- Unitat de Bioquímica, Departament de Ciències Fisiològiques, Universitat de Barcelona, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Catalunya, Spain
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Challenges and perspectives in the treatment of diabetes associated breast cancer. Cancer Treat Rev 2018; 70:98-111. [PMID: 30130687 DOI: 10.1016/j.ctrv.2018.08.004] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 08/02/2018] [Accepted: 08/09/2018] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes mellitus is one of the most common chronic disease worldwide and affects all cross-sections of the society including children, women, youth and adults. Scientific evidence has linked diabetes to higher incidence, accelerated progression and increased aggressiveness of different cancers. Among the different forms of cancer, research has reinforced a link between diabetes and the risk of breast cancer. Some studies have specifically linked diabetes to the highly aggressive, triple negative breast cancers (TNBCs) which do not respond to conventional hormonal/HER2 targeted interventions, have chances of early recurrence, metastasize, tend to be more invasive in nature and develop drug resistance. Commonly used anti-diabetic drugs, such as metformin, have recently gained importance in the treatment of breast cancer due to their proposed anti-cancer properties. Here we discuss the link between diabetes and breast cancer, the metabolic disturbances in diabetes that support the development of breast cancer, the challenges involved and future perspective and directions. We link the three main metabolic disturbances (dyslipidemia, hyperinsulinemia and hyperglycemia) that occur in diabetes to potential aberrant molecular pathways that may lead to the development of an oncogenic phenotype of the breast tissue, thereby leading to acceleration of cell growth, proliferation, migration, inflammation, angiogenesis, EMT and metastasis and inhibition of apoptosis in breast cancer cells. Furthermore, managing diabetes and treating cancer using a combination of anti-diabetic and classical anti-cancer drugs should prove to be more efficient in the treatment diabetes associated cancers.
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Bartrons R, Rodríguez-García A, Simon-Molas H, Castaño E, Manzano A, Navarro-Sabaté À. The potential utility of PFKFB3 as a therapeutic target. Expert Opin Ther Targets 2018; 22:659-674. [PMID: 29985086 DOI: 10.1080/14728222.2018.1498082] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
INTRODUCTION It has been known for over half a century that tumors exhibit an increased demand for nutrients to fuel their rapid proliferation. Interest in targeting cancer metabolism to treat the disease has been renewed in recent years with the discovery that many cancer-related pathways have a profound effect on metabolism. Considering the recent increase in our understanding of cancer metabolism and the enzymes and pathways involved, the question arises as to whether metabolism is cancer's Achilles heel. Areas covered: This review summarizes the role of 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in glycolysis, cell proliferation, and tumor growth, discussing PFKFB3 gene and isoenzyme regulation and the changes that occur in cancer and inflammatory diseases. Pharmacological options currently available for selective PFKFB3 inhibition are also reviewed. Expert opinion: PFKFB3 plays an important role in sustaining the development and progression of cancer and might represent an attractive target for therapeutic strategies. Nevertheless, clinical trials are needed to follow up on the promising results from preclinical studies with PFKFB3 inhibitors. Combination therapies with PFKFB3 inhibitors, chemotherapeutic drugs, or radiotherapy might improve the efficacy of cancer treatments targeting PFKFB3.
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Affiliation(s)
- Ramon Bartrons
- a Unitat de Bioquímica, Departament de Ciències Fisiològiques , Universitat de Barcelona, IDIBELL , Catalunya , Spain
| | - Ana Rodríguez-García
- a Unitat de Bioquímica, Departament de Ciències Fisiològiques , Universitat de Barcelona, IDIBELL , Catalunya , Spain
| | - Helga Simon-Molas
- a Unitat de Bioquímica, Departament de Ciències Fisiològiques , Universitat de Barcelona, IDIBELL , Catalunya , Spain
| | - Esther Castaño
- a Unitat de Bioquímica, Departament de Ciències Fisiològiques , Universitat de Barcelona, IDIBELL , Catalunya , Spain
| | - Anna Manzano
- a Unitat de Bioquímica, Departament de Ciències Fisiològiques , Universitat de Barcelona, IDIBELL , Catalunya , Spain
| | - Àurea Navarro-Sabaté
- a Unitat de Bioquímica, Departament de Ciències Fisiològiques , Universitat de Barcelona, IDIBELL , Catalunya , Spain
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Peng F, Li Q, Sun JY, Luo Y, Chen M, Bao Y. PFKFB3 is involved in breast cancer proliferation, migration, invasion and angiogenesis. Int J Oncol 2018; 52:945-954. [PMID: 29393396 DOI: 10.3892/ijo.2018.4257] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 12/29/2017] [Indexed: 11/05/2022] Open
Abstract
6-Phosphofructo 2-kinase/fructose 2, 6-bisphosphatase 3 (PFKFB3) has been reported to be overexpressed in human cancer tissues and to promote the proliferation and migration of cancer cells. However, the role of PFKFB3 in the progression and prognosis of breast cancer is not yet fully understood. In the present study, we investigated the specific role of PFKFB3 in breast cancer progression and its preliminary mechanisms of action. We first used an immunohistochemistry assay to determine that PFKFB3 was highly expressed in breast cancer tissues and that this high level of expression was involved in the poor overall survival of patients with breast cancer. In addition, the suppression of PFKFB3 by lentiviruses carrying shRNA against PFKFB3 (shPFKFB3) subsequently inhibited breast cancer cell (MDA-MB-231 and MDA-MB-468) proliferation, migration and invasion, and induced cell cycle G1 and S phase arrest in vitro. Moreover, PFKFB3 inhibition decreased p-AKT and increased p27 expression levels in breast cancer cells. Furthermore, PFKFB3 suppression inhibited breast cancer cell tumor xenograft growth in nude mice. We also found that PFKFB3 inhibition suppressed vascular endothelial growth factor α (VEGFα) protein expression and inhibited the angiogenic activity of human umbilical vein endothelial cells (HUVECs). On the whole, our results indicate that PFKFB3 is involved in the proliferation, migration, invasion and angiogenesis of breast cancer.
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Affiliation(s)
- Fang Peng
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Qiang Li
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jia-Yuan Sun
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China
| | - Ying Luo
- Department of Clinical Laboratory, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China
| | - Ming Chen
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, P.R. China
| | - Yong Bao
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
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Teoh ST, Lunt SY. Metabolism in cancer metastasis: bioenergetics, biosynthesis, and beyond. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE 2017; 10. [DOI: 10.1002/wsbm.1406] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 08/10/2017] [Accepted: 08/28/2017] [Indexed: 12/13/2022]
Affiliation(s)
- Shao Thing Teoh
- Department of Biochemistry and Molecular Biology; Department of Chemical Engineering and Materials Science, Michigan State University; East Lansing MI USA
| | - Sophia Y. Lunt
- Department of Biochemistry and Molecular Biology; Department of Chemical Engineering and Materials Science, Michigan State University; East Lansing MI USA
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Sreedhar A, Petruska P, Miriyala S, Panchatcharam M, Zhao Y. UCP2 overexpression enhanced glycolysis via activation of PFKFB2 during skin cell transformation. Oncotarget 2017; 8:95504-95515. [PMID: 29221144 PMCID: PMC5707038 DOI: 10.18632/oncotarget.20762] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Accepted: 08/03/2017] [Indexed: 01/01/2023] Open
Abstract
Uncoupling protein 2 (UCP2) is an inner mitochondrial membrane transporter which is often upregulated in human cancers. However, how this anion transporter affects tumorigenesis is not well understood. Using the skin cell transformation JB6 model, we demonstrated that UCP2 overexpression activated phosphofructokinase 2/fructose-2,6-bisphosphatase 2 (PFKFB2), a key regulator of glycolysis. In conjunction, upregulation of PFKFB2 expression correlated with elevated fructose 2,6-bisphosphate (Fru-2,6-P2) levels, 6-phosphofructo-1-kinase (PFK-1) activity, glucose uptake, and lactate production. Inhibiting PFKFB2 expression suppressed UCP2-mediated skin cell transformation, decreased cell proliferation, and enhanced mitochondrial respiration, while dampening aerobic glycolysis. The AKT signaling pathway was activated in the UCP2 overexpressed cells; furthermore, the activated AKT signaling contributed to the activation of PFKFB2. Whereas AKT inactivation blocked PFKFB2 activation, suggesting that AKT activation is an important step in PFKFB2 activation. Collectively, our data suggest that UCP2 is a critical regulator of cellular metabolism during cell transformation. Our data also demonstrate a potentially novel mechanism to understand UCP2's tumor-promoting role, which is through the AKT-dependent activation of PFKFB2 and thereby, the metabolic shift to glycolysis (the Warburg effect).
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Affiliation(s)
- Annapoorna Sreedhar
- Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA
| | - Petra Petruska
- Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA
| | - Sumitra Miriyala
- Department of Anatomy and Cell Biology, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA
| | - Manikandan Panchatcharam
- Department of Anatomy and Cell Biology, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA
| | - Yunfeng Zhao
- Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, USA
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Chowdhury N, Vhora I, Patel K, Doddapaneni R, Mondal A, Singh M. Liposomes co-Loaded with 6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 3 (PFKFB3) shRNA Plasmid and Docetaxel for the Treatment of non-small Cell Lung Cancer. Pharm Res 2017; 34:2371-2384. [PMID: 28875330 DOI: 10.1007/s11095-017-2244-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 07/31/2017] [Indexed: 12/13/2022]
Abstract
PURPOSE Non-small cell lung cancer is the leading cause of cancer related deaths globally. Considering the side effects and diminishing chemosensitivity to chemotherapy, novel treatment approaches are sought. Hence, we aim to develop a liposomal co-delivery system of pDNA expressing shRNA against PFKFB3 (pshPFKFB3) and docetaxel (DTX). METHODS Cationic DTX liposomes complexed with pshPFKFB3 (PSH-DL) were developed. In vitro cell line studies were performed to evaluate transfection, PFKFB3 mRNA silencing, cytotoxicity, pGP inhibition, and protein markers expression. In vivo efficacy study was performed in A549 xenograft nude mice model. RESULTS Cytotoxicity studies showed significantly enhanced anticancer activity of PSH-DL against individual treatment alone confirming the chemoenhancing effect of pshPFKFB3 on DTX activity. Fluorescence microscopy and RT-PCR showed effective transfection and RNAi by pshPFKFB3. pGP inhibition assay and western blotting revealed that PFKFB3 downregulation caused diminution of pGP activity leading to changes in cell cycle (Cdk2), survival (survivin), apoptosis (Bcl2 and cleaved caspase 3) and stress (p-JNK and p-p38) markers so that induces apoptosis by PSH-DL in NSCLC cells. PSH-DL also showed ~3.8-fold reduction in tumor volume in A549 xenograft model which was significantly higher than individual treatments alone. CONCLUSION Targeting PFKFB3 through shRNA based RNAi is a promising approach for potentiating activity of DTX in NSCLC.
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Affiliation(s)
- Nusrat Chowdhury
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, 32307, USA
| | - Imran Vhora
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, 32307, USA
| | - Ketan Patel
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, 32307, USA.,College of Pharmacy and Health Sciences, St. John's University, Jamaica, New York, 11439, USA
| | - Ravi Doddapaneni
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, 32307, USA.,Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, 33136, USA
| | - Arindam Mondal
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, 32307, USA
| | - Mandip Singh
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, 32307, USA.
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Yalcin A, Solakoglu TH, Ozcan SC, Guzel S, Peker S, Celikler S, Balaban BD, Sevinc E, Gurpinar Y, Chesney JA. 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase-3 is required for transforming growth factor β1-enhanced invasion of Panc1 cells in vitro. Biochem Biophys Res Commun 2017; 484:687-693. [DOI: 10.1016/j.bbrc.2017.01.178] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Accepted: 01/31/2017] [Indexed: 12/12/2022]
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Arts RJ, Joosten LA, Netea MG. Immunometabolic circuits in trained immunity. Semin Immunol 2016; 28:425-430. [DOI: 10.1016/j.smim.2016.09.002] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 09/16/2016] [Accepted: 09/19/2016] [Indexed: 12/21/2022]
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Abstract
In recent years there has been a growing interest among cancer biologists in cancer metabolism. This Review summarizes past and recent advances in our understanding of the reprogramming of glucose metabolism in cancer cells, which is mediated by oncogenic drivers and by the undifferentiated character of cancer cells. The reprogrammed glucose metabolism in cancer cells is required to fulfil anabolic demands. This Review discusses the possibility of exploiting the reprogrammed glucose metabolism for therapeutic approaches that selectively target cancer cells.
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Affiliation(s)
- Nissim Hay
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607 and Research and Development Section, Jesse Brown VA Medical Center, Chicago, Illinois 60612, USA
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Simon-Molas H, Calvo-Vidal MN, Castaño E, Rodríguez-García A, Navarro-Sabaté À, Bartrons R, Manzano A. Akt mediates TIGAR induction in HeLa cells following PFKFB3 inhibition. FEBS Lett 2016; 590:2915-26. [PMID: 27491040 DOI: 10.1002/1873-3468.12338] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 07/22/2016] [Accepted: 07/27/2016] [Indexed: 11/08/2022]
Abstract
Neoplastic cells metabolize higher amounts of glucose relative to normal cells in order to cover increased energetic and anabolic needs. Inhibition of the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) diminishes cancer cell proliferation and tumour growth in animals. In this work, we investigate the crosstalk between PFKFB3 and TIGAR (TP53-Induced Glycolysis and Apoptosis Regulator), a protein known to protect cells from oxidative stress. Our results show consistent TIGAR induction in HeLa cells in response to PFKFB3 knockdown. Upon PFKFB3 silencing, cells undergo oxidative stress and trigger Akt phosphorylation. This leads to induction of a TIGAR-mediated prosurvival pathway that reduces both oxidative stress and cell death. As TIGAR is known to have a role in DNA repair, it could serve as a potential target for the development of effective antineoplastic therapies.
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Affiliation(s)
- Helga Simon-Molas
- Unitat de Bioquímica, Departament de Ciències Fisiològiques, IDIBELL-Universitat de Barcelona, Spain
| | | | - Esther Castaño
- Centres Científics i Tecnològics, IDIBELL-Universitat de Barcelona, Spain
| | - Ana Rodríguez-García
- Unitat de Bioquímica, Departament de Ciències Fisiològiques, IDIBELL-Universitat de Barcelona, Spain
| | - Àurea Navarro-Sabaté
- Unitat de Bioquímica, Departament de Ciències Fisiològiques, IDIBELL-Universitat de Barcelona, Spain
| | - Ramon Bartrons
- Unitat de Bioquímica, Departament de Ciències Fisiològiques, IDIBELL-Universitat de Barcelona, Spain
| | - Anna Manzano
- Unitat de Bioquímica, Departament de Ciències Fisiològiques, IDIBELL-Universitat de Barcelona, Spain
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