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Targeting glucose metabolism as an anticancer strategy in ovarian cancer : 당 대사 조절을 통한 난소암 특이적 세포사멸 유도 및 항암제 내성 극복 연구

DC Field Value Language
dc.contributor.advisor송용상-
dc.contributor.authorHyeRan Gwak-
dc.date.accessioned2017-07-13T08:27:10Z-
dc.date.available2017-07-13T08:27:10Z-
dc.date.issued2016-02-
dc.identifier.other000000132160-
dc.identifier.urihttps://hdl.handle.net/10371/119562-
dc.description학위논문 (박사)-- 서울대학교 대학원 : 농생명공학부(바이오모듈레이션 전공), 2016. 2. 송용상.-
dc.description.abstractThere has been a growing interest in cancer metabolism for targeted therapeutic approach for cancer, however-
dc.description.abstractwe still do not fully understand the signatures of metabolic alterations and modulating factors. In current studies, we provide novel insights of glucose metabolism and regulations in ovarian cancer. Resveratrol (RSV), a natural compound from grapes, selectively impairs glucose uptake via disruption of GLUT1 localization via suppression of the action of Akt in ovarian cancer cells. Inhibition of glucose uptake by RSV leads disruption of protein N-linked glycosylation (NLG) through suppression of hexosamine biosynthetic pathway, which regulated by GSK3β. Akt/GSK3β axis involves in RSV induced NLG disruption in ovarian cancer cells. Moreover, disruption of NLG by RSV leads to endoplasmic reticulum (ER) stress-mediated apoptosis in a cancer-specific manner.
Mimicking glucose availabilities enhance cisplatin responses and suppress membrane expression of ATP-binding cassette transporters (ABC transporters), resulting from N-linked glycosylation (NLG) defect in drug-resistant ovarian cancer cells. NLG of ABC transporters is regulated by GSK3β activation through AMPK cascade in response to glucose limitation. Moreover, glucose deficiency attenuates the ovarian cancer stem-like cells (CSC) phenotypes, sphere forming capacities and stemness related gene expressions. Associated with that, glucose restriction suppresses Wnt/β-catenin signaling through decrease of β-catenin nuclear expression by GSK3β activation. Our findings provide evidence that glucose plays a pivotal role in controlling drug resistance in ovarian cancer. Hence, better understanding of differences in metabolic phenotypes between cancer cells and normal cells might offer to novel anticancer strategies.		-
dc.description.tableofcontentsChapter 1. Introduction 1
1.1. Ovarian cancer 2
1.2. Cancer metabolism 2
1.3. Protein glycosylation 3
1.4. Endoplasmic reticulum stress 4
1.5. Glucose metabolism in Ovarian cancer 5
1.6. Refferences 7

Chapter 2. Cancer-specific interruption of gluocse metabolism by resveratrol is mediated through inhibition of Akt/GLUT1 axis in ovarian cancer cells 9
Abstract 10
2.1. Introduction 11
2.2. Materials and methods 13
2.2.1. Ovarian Cancer Cell Lines and Culture Conditions 13
2.2.2. Normal Ovarian Epithelial Cell Culture 13
2.2.3. Peripheral Blood Mononuclear Cells and Red Blood Cell Isolation 14
2.2.4. Reagents and Antibodies 14
2.2.5. Glucose Uptake Assay 15
2.2.6. Cell Viability Assay 16
2.2.7. Flow Cytometric Analysis 16
2.2.8. Immunofluorescence Microscopy 17
2.2.9. RT-PCR17 17
2.2.10. Western Blotting 18
2.2.11. Transient Transfection 18
2.2.12. Statistical Analysis 19
2.3. Results 20
2.3.1. RSV inhibits glucose uptake in ovarian cancer cells 20
2.3.2. Plasma membrane localization of GLUT1 is attenuated with RSV treatment 24
2.3.3. Akt regulates GLUT1 membrane localization in ovarian cancer cells 29
2.3.4. Akt is a strong candidate for GLUT1 regulation 36
2.3.5. Dysregulated glucose uptake by RSV induces cancer cell-specific apoptosis 39
2.4. Discussion 42
2.5. References 46

Chapter 3. Resveratrol triggers ER stress-mediated apoptosis by disrupting N-linked glycosylation of proteins in ovarian cancer 50
Abstract 51
3.1. Introduction 52
3.2. Materials and methods 54
3.2.1. Ovarian Cancer Cell Lines and Culture Conditions 54
3.2.2. Peripheral Blood Mononuclear Cells and Red Blood Cell Isolation 54
3.2.3. Reagents and Antibodies 55
3.2.4. Cell death analysis 55
3.2.5. Hemolysis 56
3.2.6. Western Blotting and Lectin blotting 57
3.2.7. Small interfering RNA transfection 57
3.2.8. Transient and stable transfection 58
3.2.9. Statistical Analysis 58
3.3. Results 59
3.3.1. Interruption of protein N-linked glycosylation by resveratrol in ovarian cancer cells 59
3.3.2. Resveratrol induces ER stress–mediated apoptosis 64
3.3.3. Resveratrol inhibits glycan synthesis via hexosamine pathway with GSK3-ß activation 68
3.3.4. Akt incorporated protein glycosylation through ENTPD5 72
3.4. Discussion 81
3.5. References 85

Chapter 4. Glucose restriction enhances therapeutic responses through attenuateion of ABC transporters and stemness via GSK3β/β-catenin signaling in ovarian cancer cells 89
Abstract 90
4.1. Introduction 91
4.2. Materials and methods
4.2.1. Cell culture conditions and tumor sphere formation assay 93
4.2.2. Reagents and Antibodies 93
4.2.3. Cell death analaysis 94
4.2.4. qRT-PCR 94
4.2.5. Isolation of glycol-conjugated proteins and membrnae-associated proteins 95
4.2.6. Western Blotting and Lectin binding assay 96
4.2.7. Immunocytochemistry 96
4.2.8. Statistical Analysis 97
4.3. Results 98
4.3.1. Expressions of P-glycoprotein and ABCG2 associates with cisplatin resistance in ovarain cancer 98
4.3.2. Glucose restriction suppresses ABC transporters and enhances cisplatin responses in ovarian cancer cells 102
4.3.3. Glucose restriction disrupts ABC transporters throguh glycosylation failure 105
4.3.4. GSK3β regulates glycosylation of ABC transporters 111
4.3.5. AMPK cascade regulates the action of GSK3β 117
4.3.6. Glucose restriction attenuates ovarain cancer stemness via AMPK/GSK3β/β-catenin axis 121
4.4. Discussion 129
4.5. References 133

Chapter 5. Conclusion 138
5.1. Conclusion 139
5.2. References 143

Abstract in Korean 144		-
dc.formatapplication/pdf-
dc.format.extent3651299 bytes-
dc.format.mediumapplication/pdf-
dc.language.isoen-
dc.publisher서울대학교 대학원-
dc.subjectOvarian cancer-
dc.subjectChemoresistance-
dc.subjectGlucose metabolism-
dc.subject.ddc571-
dc.titleTargeting glucose metabolism as an anticancer strategy in ovarian cancer-
dc.title.alternative당 대사 조절을 통한 난소암 특이적 세포사멸 유도 및 항암제 내성 극복 연구-
dc.typeThesis-
dc.contributor.AlternativeAuthor곽혜란-
dc.description.degreeDoctor-
dc.citation.pages147-
dc.contributor.affiliation농업생명과학대학 농생명공학부(바이오모듈레이션전공)-
dc.date.awarded2016-02-
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