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| 1 | Glutathione metabolism is essential for self-renewal and chemoresistance of pancreatic cancer stem cells显示文摘BACKGROUND Cellular metabolism regulates stemness in health and disease.A reduced redox state is essential for self-renewal of normal and cancer stem cells(CSCs).However,while stem cells rely on glycolysis,different CSCs,including pancreatic CSCs,favor mitochondrial metabolism as their dominant energy-producing pathway.This suggests that powerful antioxidant networks must be in place to detoxify mitochondrial reactive oxygen species(ROS)and maintain stemness in oxidative CSCs.Since glutathione metabolism is critical for normal stem cell function and CSCs from breast,liver and gastric cancer show increased glutathione content,we hypothesized that pancreatic CSCs also rely on this pathway for ROS detoxification.AIM To investigate the role of glutathione metabolism in pancreatic CSCs.METHODS Primary pancreatic cancer cells of patient-derived xenografts(PDXs)were cultured in adherent or CSC-enriching sphere conditions to determine the role of glutathione metabolism in stemness.Real-time polymerase chain reaction(PCR)was used to validate RNAseq results involving glutathione metabolism genes in adherent vs spheres,as well as the expression of pluripotency-related genes following treatment.Public TCGA and GTEx RNAseq data from pancreatic cancer vs normal tissue samples were analyzed using the webserver GEPIA2.The glutathione-sensitive fluorescent probe monochlorobimane was used to determine glutathione content by fluorimetry or flow cytometry.Pharmacological inhibitors of glutathione synthesis and recycling[buthionine-sulfoximine(BSO)and 6-Aminonicotinamide(6-AN),respectively]were used to investigate the impact of glutathione depletion on CSC-enriched cultures.Staining with propidium iodide(cell cycle),Annexin-V(apoptosis)and CD133(CSC content)were determined by flow cytometry.Self-renewal was assessed by sphere formation assay and response to gemcitabine treatment was used as a readout for chemoresistance.RESULTS Analysis of our previously published RNAseq dataset E-MTAB-3808 revealed upregulation of genes involved in the KEGG(Kyoto Encyclopedia of Genes and Genomes)Pathway Glutathione Metabolism in CSC-enriched cultures compared to their differentiated counterparts.Consistently,in pancreatic cancer patient samples the expression of most of these up-regulated genes positively correlated with a stemness signature defined by NANOG,KLF4,SOX2 and OCT4 expression(P<10-5).Moreover,3 of the upregulated genes(MGST1,GPX8,GCCT)were associated with reduced disease-free survival in patients[Hazard ratio(HR)2.2-2.5;P=0.03-0.0054],suggesting a critical role for this pathway in pancreatic cancer progression.CSC-enriched sphere cultures also showed increased expression of different glutathione metabolism-related genes,as well as enhanced glutathione content in its reduced form(GSH).Glutathione depletion with BSO induced cell cycle arrest and apoptosis in spheres,and diminished the expression of stemness genes.Moreover,treatment with either BSO or the glutathione recycling inhibitor 6-AN inhibited self-renewal and the expression of the CSC marker CD133.GSH content in spheres positively correlated with intrinsic resistance to gemcitabine treatment in different PDXs r=0.96,P=5.8×1011).Additionally,CD133+cells accumulated GSH in response to gemcitabine,which was abrogated by BSO treatment(P<0.05).Combined treatment with BSO and gemcitabine-induced apoptosis in CD133+cells to levels comparable to CD133-cells and significantly diminished self-renewal(P<0.05),suggesting that chemoresistance of CSCs is partially dependent on GSH metabolism.CONCLUSION Our data suggest that pancreatic CSCs depend on glutathione metabolism.Pharmacological targeting of this pathway showed that high GSH content is essential to maintain CSC functionality in terms of self-renewal and chemoresistance. | Petra Jagust Sonia Alcala Bruno Sainz Jr Christopher Heeschen Patricia Sancho | 2020 | World Journal of Stem Cells2020，12，11： | 2 |
| 2 | Alpha/Beta interferon and gamma interferon synergize to inhibit the replication of herpes simplex virus type I 显示文摘 | Sainz B Jr Halford W P | 2002 | J Virol2002，76，11： | 1 |
| 3 | Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor显示文摘 | Sainz Jr Barretto N Martin DN | 2012 | Nature Medicine2012，18，2： | 1 |
| 4 | Identification of the NiemannPick C1-like 1cholesterol a bsorption receptor as a new hepatitis C virus entry factor显示文摘 | Sainz B Jr Barretto N Martin D N Hiraga N Imamura M Hussain S Marsh K A Yu X Chayama K Alrefai W A Uprichard S L | 2012 | Nat Med2012，18，2： | 1 |
| 5 | Alpha/Beta Interferon and Gamma Interferon Synergize To Inhibit the Replication of Herpes Simplex Virus Type 1 显示文摘 | Jr Sainz B Halford W P | 2002 | J Virol2002，76，11： | 1 |
| 6 | Multimodal treatment ehmi- nates cancer stem ceils and leads to long-term survival in primary human pancreatic cancer tissue xenografts显示文摘 | Hermann PC Trabulo SM Sainz B Jr | 2013 | PLoS One2013，8，66： | 1 |
| 7 | The proteasome and itsimplications in rheumatology 显示文摘 | Colmegna I Sainz B Jr Garry RF | 2005 | J Rheumatol2005，32，7： | 1 |
| 8 | Histologic Transformation of Benign Endometriosis to Early Epithelial Ovarian Cancer显示文摘 | Ricardo Sainz de la Cuesta John H. Eichhorn Laurel W. Rice Arlan F. Fuller Jr Najmosama Nikrui Barbara A. Goff | 1996 | Gynecologic Oncology1996，，2： | 1 |
| 9 | Identification of the Niemann-Pick Cl-like 1 cholesterol absorption recep tor as a new hepatitis C virus entry factor 显示文摘 | Sainz B Jr Barretto N Martin DN etal | 2012 | Nat Med2012，18，2： | 1 |
| 10 | Synergistic inhibition of SARS-coronavirus replication by type I and type Ⅱ IFN 显示文摘 | Mossel E C Jr Sainz B Garry R F | 2006 | Adv Exp Med Biol2006，581，： | 1 |
| 11 | Identification of the Niemann- Pick Cl-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor显示文摘 | Sainz B Jr Barretto N Martin DN | 2012 | Nat Med2012，18，2： | 1 |
| 12 | Mieroenvironmental hCAP - 18/LL- 37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment显示文摘 | Sainz B Jr Alcala S Garcia E | 2015 | Gut2015，64，12： | 1 |
| 13 | Multicenter,randomized study to optimize bowel for colon capsule endoscopy显示文摘AIM To assess the cleansing efficacy and safety of a new Colon capsule endoscopy(CCE) bowel preparation regimen.METHODS This was a multicenter,prospective,randomized,controlled study comparing two CCE regimens. Subjects were asymptomatic and average risk for colorectal cancer. The second generation CCE system(Pill Cam? COLON 2;Medtronic,Yoqneam,Israel) was utilized. Preparation regimens differed in the 1 st and 2 nd boosts with the Study regimen using oral sulfate solution(89 m L) with diatrizoate meglumine and diatrizoate sodium solution('diatrizoate solution')(boost 1 = 60 m L,boost 2 = 30 m L) and the Control regimen oral sulfate solution(89 m L) alone. The primary outcome was overall and segmental colon cleansing. Secondary outcomes included safety,polyp detection,colonic transit,CCE completion and capsule excretion ≤ 12 h. RESULTS Both regimens had similar cleansing efficacy for the whole colon(Adequate: Study = 75.9%,Control = 77.3%;P = 0.88) and individual segments. In the Study group,CCE completion was superior(Study = 90.9%,Control = 76.9%;P = 0.048) and colonic transit was more often < 40 min(Study = 21.8%,Control = 4%;P = 0.0073). More Study regimen subjects experienced adverse events(Study = 19.4%,Control = 3.4%;P = 0.0061),and this difference did not appear related to diatrizoate solution. Adverse events were primarily gastrointestinal in nature and no serious adverse events related either to the bowel preparation regimen or the capsule were observed. There was a trend toward higher polyp detection with the Study regimen,but this did not achieve statistical significance for any size category. Mean transit time through the entire gastrointestinal tract,from ingestion to excretion,was shorter with the Study regimen while mean colonic transit times were similar for both study groups.CONCLUSION A CCE bowel preparation regimen using oral sulfate solution and diatrizoate solution as a boost agent is effective,safe,and achieved superior CCE completion. | David Kastenberg Wilmot C Burch Jr David P Romeo Pankaj K Kashyap David C Pound Neophytos Papageorgiou Ignacio Fernández-Urien Sainz Carly E Sokach Douglas K Rex | 2017 | World Journal of Gastroenterology2017，23，48： | 0 |
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