|
1
|
Li Y, Wang YJ, Guo XP, Zhao HY, Ren HW, Li HY. Comprehensive analysis on the regulatory mechanism of active ingredient accumulation during fermentation process of Massa Medicata Fermentata: microbe and metabolic profiles. Front Microbiol 2025; 16:1548427. [PMID: 40143856 PMCID: PMC11936943 DOI: 10.3389/fmicb.2025.1548427] [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: 12/20/2024] [Accepted: 02/25/2025] [Indexed: 03/28/2025] Open
Abstract
Background Massa Medicata Fermentata (MMF) is a traditional medicinal/edible fermented product; however, comprehensive research on the fermentation process from a microscopic perspective remains limited. In this study, we aimed to investigate the dynamic changes and correlations of physicochemical properties, microbial communities, and metabolite profiles in different fermentation stages (0, 48, 72, and 96 h) of MMF. Methods Standard analytical tests, microbiome sequencing, broad-target metabolism, mixed standard-based mass spectrometry, and fine structure analysis were integrated to elucidate fluctuations in physicochemical, microbial, and metabolic levels during MMF fermentation. Results During the fermentation process, bacterial diversity generally shows an increasing trend, whereas fungal diversity generally shows a decreasing trend. Revealing that the differentially abundant metabolites were primarily categorized into lipids, amino acids and derivatives, phenolic acids, organic acids, flavonoids, lignans and coumarins, nucleotides and derivatives, and alkaloids. Structural equation modeling and correlation analysis indicated that two species of bacteria (Bacillus velezensis, Bacillus safensis) and four species of fungi (Apiotrichum montevideense, Geotrichum bryndzae, f_Dipodascaceae, Saccharomycopsis fibuligera) showed significant positive correlations with five types of differential metabolites, including lipids, flavonoids, phenolic acids, lignans and coumarins, and organic acids. These differential metabolites are essential components responsible for the therapeutic effects of MMF, particularly those that reach peak concentrations at 72 h of fermentation. Conclusion These findings are expected to provide a reference for developing strategies to strengthen the quality of MMF and promote its modern application.
Collapse
Affiliation(s)
- Yun Li
- School of Pharmacy, Lanzhou University, Lanzhou, China
- Lanzhou Institute for Food and Drug Control, Lanzhou, China
| | - Ya-Juan Wang
- School of Energy and Power Engineering, Lanzhou University of Technology, Lanzhou, China
| | - Xiao-Peng Guo
- School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou, China
| | - Hong-Yuan Zhao
- School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou, China
| | - Hai-Wei Ren
- School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou, China
| | - Hong-Yu Li
- School of Pharmacy, Lanzhou University, Lanzhou, China
| |
Collapse
|
|
2
|
KONG XL, LYU Q, ZHANG YQ, KANG DF, LI C, ZHANG L, GAO ZC, LIU XX, WU JB, LI YL. Effect of astragaloside IV and salvianolic acid B on antioxidant stress and vascular endothelial protection in the treatment of atherosclerosis based on metabonomics. Chin J Nat Med 2022; 20:601-613. [DOI: 10.1016/s1875-5364(22)60186-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Indexed: 11/26/2022]
|
|
3
|
Carvalho TMA, Di Molfetta D, Greco MR, Koltai T, Alfarouk KO, Reshkin SJ, Cardone RA. Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches. Cancers (Basel) 2021; 13:6135. [PMID: 34885243 PMCID: PMC8657427 DOI: 10.3390/cancers13236135] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/26/2021] [Accepted: 12/01/2021] [Indexed: 12/14/2022] Open
Abstract
Currently, the median overall survival of PDAC patients rarely exceeds 1 year and has an overall 5-year survival rate of about 9%. These numbers are anticipated to worsen in the future due to the lack of understanding of the factors involved in its strong chemoresistance. Chemotherapy remains the only treatment option for most PDAC patients; however, the available therapeutic strategies are insufficient. The factors involved in chemoresistance include the development of a desmoplastic stroma which reprograms cellular metabolism, and both contribute to an impaired response to therapy. PDAC stroma is composed of immune cells, endothelial cells, and cancer-associated fibroblasts embedded in a prominent, dense extracellular matrix associated with areas of hypoxia and acidic extracellular pH. While multiple gene mutations are involved in PDAC initiation, this desmoplastic stroma plays an important role in driving progression, metastasis, and chemoresistance. Elucidating the mechanisms underlying PDAC resistance are a prerequisite for designing novel approaches to increase patient survival. In this review, we provide an overview of the stromal features and how they contribute to the chemoresistance in PDAC treatment. By highlighting new paradigms in the role of the stromal compartment in PDAC therapy, we hope to stimulate new concepts aimed at improving patient outcomes.
Collapse
Affiliation(s)
- Tiago M. A. Carvalho
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
| | - Daria Di Molfetta
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
| | - Maria Raffaella Greco
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
| | | | - Khalid O. Alfarouk
- Al-Ghad International College for Applied Medical Sciences, Al-Madinah Al-Munwarah 42316, Saudi Arabia;
| | - Stephan J. Reshkin
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
| | - Rosa A. Cardone
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (D.D.M.); (M.R.G.); (S.J.R.); (R.A.C.)
| |
Collapse
|
|
4
|
Fu Y, Ricciardiello F, Yang G, Qiu J, Huang H, Xiao J, Cao Z, Zhao F, Liu Y, Luo W, Chen G, You L, Chiaradonna F, Zheng L, Zhang T. The Role of Mitochondria in the Chemoresistance of Pancreatic Cancer Cells. Cells 2021; 10:497. [PMID: 33669111 PMCID: PMC7996512 DOI: 10.3390/cells10030497] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/16/2021] [Accepted: 02/14/2021] [Indexed: 02/06/2023] Open
Abstract
The first-line chemotherapies for patients with unresectable pancreatic cancer (PC) are 5-fluorouracil (5-FU) and gemcitabine therapy. However, due to chemoresistance the prognosis of patients with PC has not been significantly improved. Mitochondria are essential organelles in eukaryotes that evolved from aerobic bacteria. In recent years, many studies have shown that mitochondria play important roles in tumorigenesis and may act as chemotherapeutic targets in PC. In addition, according to recent studies, mitochondria may play important roles in the chemoresistance of PC by affecting apoptosis, metabolism, mtDNA metabolism, and mitochondrial dynamics. Interfering with some of these factors in mitochondria may improve the sensitivity of PC cells to chemotherapeutic agents, such as gemcitabine, making mitochondria promising targets for overcoming chemoresistance in PC.
Collapse
Affiliation(s)
- Yibo Fu
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Francesca Ricciardiello
- Department of Biotechnology and Bioscience, University of Milano Bicocca, 20126 Milano, Italy;
| | - Gang Yang
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Jiangdong Qiu
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Hua Huang
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Jianchun Xiao
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Zhe Cao
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Fangyu Zhao
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Yueze Liu
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Wenhao Luo
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Guangyu Chen
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Lei You
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
| | - Ferdinando Chiaradonna
- Department of Biotechnology and Bioscience, University of Milano Bicocca, 20126 Milano, Italy;
| | - Lianfang Zheng
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China;
| | - Taiping Zhang
- General Surgery Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (Y.F.); (G.Y.); (J.Q.); (H.H.); (J.X.); (Z.C.); (F.Z.); (Y.L.); (W.L.); (G.C.); (L.Y.)
- Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| |
Collapse
|
|
5
|
Grasso C, Jansen G, Giovannetti E. Drug resistance in pancreatic cancer: Impact of altered energy metabolism. Crit Rev Oncol Hematol 2017; 114:139-152. [PMID: 28477742 DOI: 10.1016/j.critrevonc.2017.03.026] [Citation(s) in RCA: 181] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 03/21/2017] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is a highly deadly disease: almost all patients develop metastases and conventional treatments have little impact on survival. Therapeutically, this tumor is poorly responsive, largely due to drug resistance. Accumulating evidence suggest that this chemoresistance is intimately linked to specific metabolic aberrations of pancreatic cancer cells, notably an increased use of glucose and the amino acid glutamine fueling anabolic processes. Altered metabolism contributes also to modulation of apoptosis, angiogenesis and drug targets, conferring a resistant phenotype. As a modality to overcome chemoresistance, a variety of experimental compounds inhibiting key metabolic pathways emerged as a promising approach to potentiate the standard treatments for pancreatic cancer in preclinical studies. These results warrant confirmation in clinical trials. Thus, this review summarizes the impact of metabolic aberrations from the perspective of drug resistance and discusses possible novel applications of metabolic inhibition for the development of more effective drugs against pancreatic cancer.
Collapse
Affiliation(s)
- Cristoforo Grasso
- Laboratory Medical Oncology, Department of Medical Oncology VU University Medical Center (VUmc), Amsterdam, The Netherlands
| | - Gerrit Jansen
- Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VUmc, Amsterdam, The Netherlands
| | - Elisa Giovannetti
- Laboratory Medical Oncology, Department of Medical Oncology VU University Medical Center (VUmc), Amsterdam, The Netherlands; Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa, Italy.
| |
Collapse
|
|
6
|
Chan AKC, Bruce JIE, Siriwardena AK. Glucose metabolic phenotype of pancreatic cancer. World J Gastroenterol 2016; 22:3471-3485. [PMID: 27022229 PMCID: PMC4806205 DOI: 10.3748/wjg.v22.i12.3471] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 01/30/2016] [Accepted: 03/02/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To construct a global “metabolic phenotype” of pancreatic ductal adenocarcinoma (PDAC) reflecting tumour-related metabolic enzyme expression.
METHODS: A systematic review of the literature was performed using OvidSP and PubMed databases using keywords “pancreatic cancer” and individual glycolytic and mitochondrial oxidative phosphorylation (MOP) enzymes. Both human and animal studies investigating the oncological effect of enzyme expression changes and inhibitors in both an in vitro and in vivo setting were included in the review. Data reporting changes in enzyme expression and the effects on PDAC cells, such as survival and metastatic potential, were extracted to construct a metabolic phenotype.
RESULTS: Seven hundred and ten papers were initially retrieved, and were screened to meet the review inclusion criteria. 107 unique articles were identified as reporting data involving glycolytic enzymes, and 28 articles involving MOP enzymes in PDAC. Data extraction followed a pre-defined protocol. There is consistent over-expression of glycolytic enzymes and lactate dehydrogenase in keeping with the Warburg effect to facilitate rapid adenosine-triphosphate production from glycolysis. Certain isoforms of these enzymes were over-expressed specifically in PDAC. Altering expression levels of HK, PGI, FBA, enolase, PK-M2 and LDA-A with metabolic inhibitors have shown a favourable effect on PDAC, thus identifying these as potential therapeutic targets. However, the Warburg effect on MOP enzymes is less clear, with different expression levels at different points in the Krebs cycle resulting in a fundamental change of metabolite levels, suggesting that other essential anabolic pathways are being stimulated.
CONCLUSION: Further characterisation of the PDAC metabolic phenotype is necessary as currently there are few clinical studies and no successful clinical trials targeting metabolic enzymes.
Collapse
|
|
7
|
Grose JH, Langston K, Wang X, Squires S, Mustafi SB, Hayes W, Neubert J, Fischer SK, Fasano M, Saunders GM, Dai Q, Christians E, Lewandowski ED, Ping P, Benjamin IJ. Characterization of the Cardiac Overexpression of HSPB2 Reveals Mitochondrial and Myogenic Roles Supported by a Cardiac HspB2 Interactome. PLoS One 2015; 10:e0133994. [PMID: 26465331 PMCID: PMC4605610 DOI: 10.1371/journal.pone.0133994] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 07/03/2015] [Indexed: 01/26/2023] Open
Abstract
Small Heat Shock Proteins (sHSPs) are molecular chaperones that transiently interact with other proteins, thereby assisting with quality control of proper protein folding and/or degradation. They are also recruited to protect cells from a variety of stresses in response to extreme heat, heavy metals, and oxidative-reductive stress. Although ten human sHSPs have been identified, their likely diverse biological functions remain an enigma in health and disease, and much less is known about non-redundant roles in selective cells and tissues. Herein, we set out to comprehensively characterize the cardiac-restricted Heat Shock Protein B-2 (HspB2), which exhibited ischemic cardioprotection in transgenic overexpressing mice including reduced infarct size and maintenance of ATP levels. Global yeast two-hybrid analysis using HspB2 (bait) and a human cardiac library (prey) coupled with co-immunoprecipitation studies for mitochondrial target validation revealed the first HspB2 “cardiac interactome” to contain many myofibril and mitochondrial-binding partners consistent with the overexpression phenotype. This interactome has been submitted to the Biological General Repository for Interaction Datasets (BioGRID). A related sHSP chaperone HspB5 had only partially overlapping binding partners, supporting specificity of the interactome as well as non-redundant roles reported for these sHSPs. Evidence that the cardiac yeast two-hybrid HspB2 interactome targets resident mitochondrial client proteins is consistent with the role of HspB2 in maintaining ATP levels and suggests new chaperone-dependent functions for metabolic homeostasis. One of the HspB2 targets, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), has reported roles in HspB2 associated phenotypes including cardiac ATP production, mitochondrial function, and apoptosis, and was validated as a potential client protein of HspB2 through chaperone assays. From the clientele and phenotypes identified herein, it is tempting to speculate that small molecule activators of HspB2 might be deployed to mitigate mitochondrial related diseases such as cardiomyopathy and neurodegenerative disease.
Collapse
Affiliation(s)
- Julianne H. Grose
- Microbiology and Molecular Biology Department, Brigham Young University, Provo, UT, 84602, United States of America
- * E-mail: (JHG); (IJB)
| | - Kelsey Langston
- Microbiology and Molecular Biology Department, Brigham Young University, Provo, UT, 84602, United States of America
| | - Xiaohui Wang
- Laboratory of Cardiac Disease, Redox Signaling and Cell Regeneration, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT, 84132, United States of America
| | - Shayne Squires
- Laboratory of Cardiac Disease, Redox Signaling and Cell Regeneration, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT, 84132, United States of America
- Division of Cardiovascular Medicine, Dept. of Medicine, Medical College of Wisconsin, Milwaukee, WI, 53226, United States of America
| | - Soumyajit Banerjee Mustafi
- Laboratory of Cardiac Disease, Redox Signaling and Cell Regeneration, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT, 84132, United States of America
| | - Whitney Hayes
- Microbiology and Molecular Biology Department, Brigham Young University, Provo, UT, 84602, United States of America
| | - Jonathan Neubert
- Microbiology and Molecular Biology Department, Brigham Young University, Provo, UT, 84602, United States of America
| | - Susan K. Fischer
- Program in Integrative Cardiac Metabolism, Center for Cardiovascular Research, University of Illinois at Chicago College of Medicine, Chicago, IL, 60612, United States of America
| | - Matthew Fasano
- Program in Integrative Cardiac Metabolism, Center for Cardiovascular Research, University of Illinois at Chicago College of Medicine, Chicago, IL, 60612, United States of America
| | - Gina Moore Saunders
- Laboratory of Cardiac Disease, Redox Signaling and Cell Regeneration, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT, 84132, United States of America
| | - Qiang Dai
- Division of Cardiovascular Medicine, Dept. of Medicine, Medical College of Wisconsin, Milwaukee, WI, 53226, United States of America
| | - Elisabeth Christians
- Laboratory of Cardiac Disease, Redox Signaling and Cell Regeneration, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT, 84132, United States of America
| | - E. Douglas Lewandowski
- Program in Integrative Cardiac Metabolism, Center for Cardiovascular Research, University of Illinois at Chicago College of Medicine, Chicago, IL, 60612, United States of America
| | - Peipei Ping
- UCLA Departments of Physiology, Medicine, and Cardiology, Los Angeles, CA, 90095, United States of America
| | - Ivor J. Benjamin
- Laboratory of Cardiac Disease, Redox Signaling and Cell Regeneration, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT, 84132, United States of America
- Division of Cardiovascular Medicine, Dept. of Medicine, Medical College of Wisconsin, Milwaukee, WI, 53226, United States of America
- * E-mail: (JHG); (IJB)
| |
Collapse
|
|
8
|
Alfarouk KO, Verduzco D, Rauch C, Muddathir AK, Adil HHB, Elhassan GO, Ibrahim ME, David Polo Orozco J, Cardone RA, Reshkin SJ, Harguindey S. Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question. Oncoscience 2014; 1:777-802. [PMID: 25621294 PMCID: PMC4303887 DOI: 10.18632/oncoscience.109] [Citation(s) in RCA: 162] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 12/14/2014] [Indexed: 12/15/2022] Open
Abstract
Cancer cells acquire an unusual glycolytic behavior relative, to a large extent, to their intracellular alkaline pH (pHi). This effect is part of the metabolic alterations found in most, if not all, cancer cells to deal with unfavorable conditions, mainly hypoxia and low nutrient supply, in order to preserve its evolutionary trajectory with the production of lactate after ten steps of glycolysis. Thus, cancer cells reprogram their cellular metabolism in a way that gives them their evolutionary and thermodynamic advantage. Tumors exist within a highly heterogeneous microenvironment and cancer cells survive within any of the different habitats that lie within tumors thanks to the overexpression of different membrane-bound proton transporters. This creates a highly abnormal and selective proton reversal in cancer cells and tissues that is involved in local cancer growth and in the metastatic process. Because of this environmental heterogeneity, cancer cells within one part of the tumor may have a different genotype and phenotype than within another part. This phenomenon has frustrated the potential of single-target therapy of this type of reductionist therapeutic approach over the last decades. Here, we present a detailed biochemical framework on every step of tumor glycolysis and then proposea new paradigm and therapeutic strategy based upon the dynamics of the hydrogen ion in cancer cells and tissues in order to overcome the old paradigm of one enzyme-one target approach to cancer treatment. Finally, a new and integral explanation of the Warburg effect is advanced.
Collapse
Affiliation(s)
| | | | - Cyril Rauch
- University of Nottingham, Sutton Bonington, Leicestershire, Nottingham, UK
| | | | | | - Gamal O. Elhassan
- Unizah Pharmacy Collage, Qassim University, Unizah, AL-Qassim, King of Saudi Arabia
- Omdurman Islamic University, Omdurman, Sudan
| | | | | | | | | | | |
Collapse
|
|
9
|
Evaluation of immune and apoptosis related gene responses using an RNAi approach in vaccinated Penaeus monodon during oral WSSV infection. Mar Genomics 2014; 18 Pt A:55-65. [DOI: 10.1016/j.margen.2014.05.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 05/09/2014] [Accepted: 05/09/2014] [Indexed: 01/10/2023]
|
|
10
|
Martínez-Fábregas J, Díaz-Moreno I, González-Arzola K, Janocha S, Navarro JA, Hervás M, Bernhardt R, Velázquez-Campoy A, Díaz-Quintana A, De la Rosa MA. Structural and functional analysis of novel human cytochrome C targets in apoptosis. Mol Cell Proteomics 2014; 13:1439-56. [PMID: 24643968 DOI: 10.1074/mcp.m113.034322] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Since the first description of apoptosis four decades ago, great efforts have been made to elucidate, both in vivo and in vitro, the molecular mechanisms involved in its regulation. Although the role of cytochrome c during apoptosis is well established, relatively little is known about its participation in signaling pathways in vivo due to its essential role during respiration. To obtain a better understanding of the role of cytochrome c in the onset of apoptosis, we used a proteomic approach based on affinity chromatography with cytochrome c as bait in this study. In this approach, novel cytochrome c interaction partners were identified whose in vivo interaction and cellular localization were facilitated through bimolecular fluorescence complementation. Modeling of the complex interface between cytochrome c and its counterparts indicated the involvement of the surface surrounding the heme crevice of cytochrome c, in agreement with the vast majority of known redox adducts of cytochrome c. However, in contrast to the high turnover rate of the mitochondrial cytochrome c redox adducts, those occurring under apoptosis led to the formation of stable nucleo-cytoplasmic ensembles, as inferred mainly from surface plasmon resonance and nuclear magnetic resonance measurements, which permitted us to corroborate the formation of such complexes in vitro. The results obtained suggest that human cytochrome c interacts with pro-survival, anti-apoptotic proteins following its release into the cytoplasm. Thus, cytochrome c may interfere with cell survival pathways and unlock apoptosis in order to prevent the spatial and temporal coexistence of antagonist signals.
Collapse
Affiliation(s)
- Jonathan Martínez-Fábregas
- From the ‡Instituto de Bioquímica Vegetal y Fotosíntesis, cicCartuja, Universidad de Sevilla-CSIC, Avda. Américo Vespucio 49, Sevilla 41092, Spain
| | - Irene Díaz-Moreno
- From the ‡Instituto de Bioquímica Vegetal y Fotosíntesis, cicCartuja, Universidad de Sevilla-CSIC, Avda. Américo Vespucio 49, Sevilla 41092, Spain
| | - Katiuska González-Arzola
- From the ‡Instituto de Bioquímica Vegetal y Fotosíntesis, cicCartuja, Universidad de Sevilla-CSIC, Avda. Américo Vespucio 49, Sevilla 41092, Spain
| | - Simon Janocha
- §Institut für Biochemie, Universität des Saarlandes, Campus B2.2, D-66123 Saarbrücken, Germany
| | - José A Navarro
- From the ‡Instituto de Bioquímica Vegetal y Fotosíntesis, cicCartuja, Universidad de Sevilla-CSIC, Avda. Américo Vespucio 49, Sevilla 41092, Spain
| | - Manuel Hervás
- From the ‡Instituto de Bioquímica Vegetal y Fotosíntesis, cicCartuja, Universidad de Sevilla-CSIC, Avda. Américo Vespucio 49, Sevilla 41092, Spain
| | - Rita Bernhardt
- §Institut für Biochemie, Universität des Saarlandes, Campus B2.2, D-66123 Saarbrücken, Germany
| | - Adrián Velázquez-Campoy
- ¶Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint-Unit IQFR-CSIC-BIFI, Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, Zaragoza, Spain, and Fundacion ARAID, Government of Aragon, Zaragoza, Spain
| | - Antonio Díaz-Quintana
- From the ‡Instituto de Bioquímica Vegetal y Fotosíntesis, cicCartuja, Universidad de Sevilla-CSIC, Avda. Américo Vespucio 49, Sevilla 41092, Spain
| | - Miguel A De la Rosa
- From the ‡Instituto de Bioquímica Vegetal y Fotosíntesis, cicCartuja, Universidad de Sevilla-CSIC, Avda. Américo Vespucio 49, Sevilla 41092, Spain;
| |
Collapse
|
|
11
|
Abstract
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has long been recognized as an important enzyme for energy metabolism and the production of ATP and pyruvate through anaerobic glycolysis in the cytoplasm. Recent studies have shown that GAPDH has multiple functions independent of its role in energy metabolism. Although increased GAPDH gene expression and enzymatic function is associated with cell proliferation and tumourigenesis, conditions such as oxidative stress impair GAPDH catalytic activity and lead to cellular aging and apoptosis. The mechanism(s) underlying the effects of GAPDH on cellular proliferation remains unclear, yet much evidence has been accrued that demonstrates a variety of interacting partners for GAPDH, including proteins, various RNA species and telomeric DNA. The present mini review summarizes recent findings relating to the extraglycolytic functions of GAPDH and highlights the significant role this enzyme plays in regulating both cell survival and apoptotic death.
Collapse
Affiliation(s)
- Craig Nicholls
- Molecular Signalling Laboratory, Murdoch Childrens Research Institute, Monash University, Melbourne, Victoria, Australia
| | | | | |
Collapse
|
|
12
|
Apparent versus true gene expression changes of three hypoxia-related genes in autopsy derived tissue and the importance of normalisation. Int J Legal Med 2012; 127:335-44. [DOI: 10.1007/s00414-012-0787-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Accepted: 10/16/2012] [Indexed: 01/21/2023]
|
|
13
|
Kim SY, Kim MJ, Jung H, Kim WK, Kwon SO, Son MJ, Jang IS, Choi JS, Park SG, Park BC, Han YM, Lee SC, Cho YS, Bae KH. Comparative Proteomic Analysis of Human Somatic Cells, Induced Pluripotent Stem Cells, and Embryonic Stem Cells. Stem Cells Dev 2012; 21:1272-86. [DOI: 10.1089/scd.2011.0243] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Affiliation(s)
- Sun Young Kim
- Medical Proteomics Research Center, KRIBB, Daejeon, South Korea
- Department of Biological Sciences, KAIST, Daejeon, South Korea
| | - Min-Jeong Kim
- Development and Differentiation Research Center, KRIBB, Daejeon, South Korea
| | - Hyeyun Jung
- Medical Proteomics Research Center, KRIBB, Daejeon, South Korea
| | - Won Kon Kim
- Medical Proteomics Research Center, KRIBB, Daejeon, South Korea
| | - Sang Oh Kwon
- Proteome Research Team, Korea Basic Science Institute, Daejeon, South Korea
| | - Myung Jin Son
- Development and Differentiation Research Center, KRIBB, Daejeon, South Korea
| | - Ik-Soon Jang
- Proteome Research Team, Korea Basic Science Institute, Daejeon, South Korea
| | - Jong-Soon Choi
- Proteome Research Team, Korea Basic Science Institute, Daejeon, South Korea
| | - Sung Goo Park
- Medical Proteomics Research Center, KRIBB, Daejeon, South Korea
| | | | - Yong-Mahn Han
- Department of Biological Sciences, KAIST, Daejeon, South Korea
| | - Sang Chul Lee
- Medical Proteomics Research Center, KRIBB, Daejeon, South Korea
| | - Yee Sook Cho
- Development and Differentiation Research Center, KRIBB, Daejeon, South Korea
| | - Kwang-Hee Bae
- Medical Proteomics Research Center, KRIBB, Daejeon, South Korea
| |
Collapse
|
|
14
|
Herling A, König M, Bulik S, Holzhütter HG. Enzymatic features of the glucose metabolism in tumor cells. FEBS J 2011; 278:2436-59. [PMID: 21564549 DOI: 10.1111/j.1742-4658.2011.08174.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Many tumor types exhibit an impaired Pasteur effect, i.e. despite the presence of oxygen, glucose is consumed at an extraordinarily high rate compared with the tissue from which they originate - the so-called 'Warburg effect'. Glucose has to serve as the source for a diverse array of cellular functions, including energy production, synthesis of nucleotides and lipids, membrane synthesis and generation of redox equivalents for antioxidative defense. Tumor cells acquire specific enzyme-regulatory mechanisms to direct the main flux of glucose carbons to those pathways most urgently required under challenging external conditions such as varying substrate availability, presence of anti-cancer drugs or different phases of the cell cycle. In this review we summarize the currently available information on tumor-specific expression, activity and kinetic properties of enzymes involved in the main pathways of glucose metabolism with due regard to the explanation of the regulatory basis and physiological significance of the Warburg effect. We conclude that, besides the expression level of the metabolic enzymes involved in the glucose metabolism of tumor cells, the unique tumor-specific pattern of isozymes and accompanying changes in the metabolic regulation below the translation level enable tumor cells to drain selfishly the blood glucose pool that non-transformed cells use as sparingly as possible.
Collapse
Affiliation(s)
- Anique Herling
- University Medicine Berlin (Charité), Institute of Biochemistry, Berlin, Germany
| | | | | | | |
Collapse
|
|
15
|
Sun L, Li HM, Seufferheld MJ, Walters KR, Margam VM, Jannasch A, Diaz N, Riley CP, Sun W, Li YF, Muir WM, Xie J, Wu J, Zhang F, Chen JY, Barker EL, Adamec J, Pittendrigh BR. Systems-scale analysis reveals pathways involved in cellular response to methamphetamine. PLoS One 2011; 6:e18215. [PMID: 21533132 PMCID: PMC3080363 DOI: 10.1371/journal.pone.0018215] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Accepted: 02/28/2011] [Indexed: 12/20/2022] Open
Abstract
Background Methamphetamine (METH), an abused illicit drug, disrupts many cellular
processes, including energy metabolism, spermatogenesis, and maintenance of
oxidative status. However, many components of the molecular underpinnings of
METH toxicity have yet to be established. Network analyses of integrated
proteomic, transcriptomic and metabolomic data are particularly well suited
for identifying cellular responses to toxins, such as METH, which might
otherwise be obscured by the numerous and dynamic changes that are
induced. Methodology/Results We used network analyses of proteomic and transcriptomic data to evaluate
pathways in Drosophila melanogaster that are affected by
acute METH toxicity. METH exposure caused changes in the expression of genes
involved with energy metabolism, suggesting a Warburg-like effect (aerobic
glycolysis), which is normally associated with cancerous cells. Therefore,
we tested the hypothesis that carbohydrate metabolism plays an important
role in METH toxicity. In agreement with our hypothesis, we observed that
increased dietary sugars partially alleviated the toxic effects of METH. Our
systems analysis also showed that METH impacted genes and proteins known to
be associated with muscular homeostasis/contraction, maintenance of
oxidative status, oxidative phosphorylation, spermatogenesis, iron and
calcium homeostasis. Our results also provide numerous candidate genes for
the METH-induced dysfunction of spermatogenesis, which have not been
previously characterized at the molecular level. Conclusion Our results support our overall hypothesis that METH causes a toxic syndrome
that is characterized by the altered carbohydrate metabolism, dysregulation
of calcium and iron homeostasis, increased oxidative stress, and disruption
of mitochondrial functions.
Collapse
Affiliation(s)
- Lijie Sun
- Department of Entomology, University of Illinois at Urbana-Champaign,
Urbana, Illinois, United States of America
- Synthetic Biology & Bioenergy, J. Craig Venter Institute, San Diego,
California, United States of America
- Department of Entomology, Purdue University, West Lafayette, Indiana,
United States of America
| | - Hong-Mei Li
- Department of Entomology, University of Illinois at Urbana-Champaign,
Urbana, Illinois, United States of America
| | - Manfredo J. Seufferheld
- Department of Crop Sciences, University of Illinois at Urbana-Champaign,
Urbana, Illinois, United States of America
| | - Kent R. Walters
- Department of Entomology, University of Illinois at Urbana-Champaign,
Urbana, Illinois, United States of America
| | - Venu M. Margam
- Department of Entomology, Purdue University, West Lafayette, Indiana,
United States of America
| | - Amber Jannasch
- Metabolomics Profiling Facility at Bindley Bioscience Center, Purdue
University, West Lafayette, Indiana, United States of America
| | - Naomi Diaz
- Metabolomics Profiling Facility at Bindley Bioscience Center, Purdue
University, West Lafayette, Indiana, United States of America
| | - Catherine P. Riley
- Metabolomics Profiling Facility at Bindley Bioscience Center, Purdue
University, West Lafayette, Indiana, United States of America
| | - Weilin Sun
- Department of Entomology, University of Illinois at Urbana-Champaign,
Urbana, Illinois, United States of America
| | - Yueh-Feng Li
- Department of Entomology, Purdue University, West Lafayette, Indiana,
United States of America
- Chung Hwa College of Medical Technology, Jen-Te Hsiang, Tainan,
Taiwan
| | - William M. Muir
- Department of Animal Sciences, Purdue University, West Lafayette,
Indiana, United States of America
| | - Jun Xie
- Department of Statistics, Purdue University, West Lafayette, Indiana,
United States of America
| | - Jing Wu
- Department of Statistics, Carnegie Mellon University, Pittsburgh,
Pennsylvania, United States of America
| | - Fan Zhang
- School of Informatics, Indiana University, Indianapolis, Indiana, United
States of America
| | - Jake Y. Chen
- School of Informatics, Indiana University, Indianapolis, Indiana, United
States of America
| | - Eric L. Barker
- Medicinal Chemistry and Molecular Pharmacology, Purdue University, West
Lafayette, Indiana, United States of America
| | - Jiri Adamec
- Department of Biochemistry, University of Nebraska, Lincoln, Nebraska,
United States of America
| | - Barry R. Pittendrigh
- Department of Entomology, University of Illinois at Urbana-Champaign,
Urbana, Illinois, United States of America
- * E-mail:
| |
Collapse
|
|
16
|
Tunio SA, Oldfield NJ, Ala'Aldeen DAA, Wooldridge KG, Turner DPJ. The role of glyceraldehyde 3-phosphate dehydrogenase (GapA-1) in Neisseria meningitidis adherence to human cells. BMC Microbiol 2010; 10:280. [PMID: 21062461 PMCID: PMC2994834 DOI: 10.1186/1471-2180-10-280] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2010] [Accepted: 11/09/2010] [Indexed: 12/27/2022] Open
Abstract
Background Glyceraldehyde 3-phosphate dehydrogenases (GAPDHs) are cytoplasmic glycolytic enzymes, which although lacking identifiable secretion signals, have also been found localized to the surface of several bacteria (and some eukaryotic organisms); where in some cases they have been shown to contribute to the colonization and invasion of host tissues. Neisseria meningitidis is an obligate human nasopharyngeal commensal which can cause life-threatening infections including septicaemia and meningitis. N. meningitidis has two genes, gapA-1 and gapA-2, encoding GAPDH enzymes. GapA-1 has previously been shown to be up-regulated on bacterial contact with host epithelial cells and is accessible to antibodies on the surface of capsule-permeabilized meningococcal cells. The aims of this study were: 1) to determine whether GapA-1 was expressed across different strains of N. meningitidis; 2) to determine whether GapA-1 surface accessibility to antibodies was dependant on the presence of capsule; 3) to determine whether GapA-1 can influence the interaction of meningococci and host cells, particularly in the key stages of adhesion and invasion. Results In this study, expression of GapA-1 was shown to be well conserved across diverse isolates of Neisseria species. Flow cytometry confirmed that GapA-1 could be detected on the cell surface, but only in a siaD-knockout (capsule-deficient) background, suggesting that GapA-1 is inaccessible to antibody in in vitro-grown encapsulated meningococci. The role of GapA-1 in meningococcal pathogenesis was addressed by mutational analysis and functional complementation. Loss of GapA-1 did not affect the growth of the bacterium in vitro. However, a GapA-1 deficient mutant showed a significant reduction in adhesion to human epithelial and endothelial cells compared to the wild-type and complemented mutant. A similar reduction in adhesion levels was also apparent between a siaD-deficient meningococcal strain and an isogenic siaD gapA-1 double mutant. Conclusions Our data demonstrates that meningococcal GapA-1 is a constitutively-expressed, highly-conserved surface-exposed protein which is antibody-accessible only in the absence of capsule. Mutation of GapA-1 does not affect the in vitro growth rate of N. meningitidis, but significantly affects the ability of the organism to adhere to human epithelial and endothelial cells in a capsule-independent process suggesting a role in the pathogenesis of meningococcal infection.
Collapse
Affiliation(s)
- Sarfraz A Tunio
- Molecular Bacteriology and Immunology Group, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, NG7 2RD, UK
| | | | | | | | | |
Collapse
|
|
17
|
Gawinecka J, Dieks J, Asif AR, Carimalo J, Heinemann U, Streich JH, Dihazi H, Schulz-Schaeffer W, Zerr I. Codon 129 polymorphism specific cerebrospinal fluid proteome pattern in sporadic Creutzfeldt-Jakob disease and the implication of glycolytic enzymes in prion-induced pathology. J Proteome Res 2010; 9:5646-57. [PMID: 20866111 DOI: 10.1021/pr1004604] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cerebrospinal fluid (CSF) contains a dynamic and complex mixture of proteins, which can reflect a physiological and pathological state of the central nervous system. In our present study, we show CSF protein patterns from patients with the two most frequent subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) defined by the codon 129 genotype (MM, MV, and VV) and the protease-resistant form of prion protein (type 1 and type 2). The densitometric analysis of 2D gels showed up-regulation of 27 and down-regulation of 3 proteins in the MM-sCJD as well as the up-regulation of 24 proteins in the VV-sCJD as compared to nondemented control. Almost 40% of sCJD specific regulated proteins in CSF are involved in glucose metabolism, regardless of the codon 129 polymorphism. The increase in CSF levels of lactate dehydrogenase (LDH), glucose-6-phosphate isomerase (G6PI), and fructose-bisphosphate aldolase A (ALDOA) were validated on a larger group of sCJD patients including three possible codon 129 polymorphism carriers and three control groups consisting of nondemented, neurological cases as well as patients suffering from Alzheimer's disease or vascular dementia. Subsequently, the abundance of these glycolytic enzymes in the brain as well as their cellular localization were determined. This study demonstrates for the first time the implication of G6PI in prion-induced pathology as well as its cellular translocalization in sCJD. The identification of sCJD-regulated proteins in CSF of living symptomatic patients in our study can broaden our knowledge about pathological processes occurring in sCJD, as they are still not fully understood.
Collapse
Affiliation(s)
- Joanna Gawinecka
- Department of Clinical Chemistry, Medical Center Georg-August University, Goettingen, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|