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Role of AMPK in regulation of oxaliplatin-resistant human colorectal cancer
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.advisor | 김소희 | - |
| dc.contributor.author | 정예서 | - |
| dc.date.accessioned | 2025-01-25T01:36:08Z | - |
| dc.date.available | 2025-01-25T01:36:08Z | - |
| dc.date.issued | 2023-02 | - |
| dc.identifier.other | 32499 | - |
| dc.identifier.uri | https://dspace.ajou.ac.kr/handle/2018.oak/24642 | - |
| dc.description | 학위논문(석사)--바이오헬스규제과학과,2023. 2 | - |
| dc.description.abstract | 옥살리플라틴(Oxaliplatin)은 DNA 복제 및 전사를 방해할 수 있는 백금 유사체입니다. 옥살리플라틴의 지속적인 노출은 화학적 내성을 초래하지만, 이러한 메커니즘은 잘 알려져 있지 않습니다. 본 연구에서는 약물 농도를 최대 2.5 μM 까지 단계적으로 증가시켜 HCT116, HT29, SW480, SW620의 옥살리플라틴 내성 (OR) 대장암 세포를 확립하였습니다. 옥살리플라틴에 의한 50% 세포 성장 억제 농도(IC50)값은 각각 모세포(PT)에 비해 옥살리플라틴 내성 세포(OR)에서 4.40-12.7배 높았습니다. PT 세포에서는 phospho-Akt와 phospho-mammalian target of rapamycin (mTOR)가 감소하였으나 OR 세포에서는 옥살리플라틴에 반응하여 과발현되었습니다. 또한, PT 세포에서 phospho-AMP-activated protein kinase (AMPK)의 옥살리플라틴 매개 감소는 autophagy를 유도했습니다. 대조적으로, OR 세포에서 phospho-AMPK의 증가는 LC3B의 감소를 동반하여 해당과정에 관여하는 단백질인 glucose transporter 1 (GLUT1), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) 및 phosphofructokinase (PFK1)의 활성을 더 유도하여 세포 생존을 매개하였습니다. OR 세포에서 AMPK의 억제는 Akt/mTOR 경로를 불활성화시키고, GLUT1, PFKFB3 및 PFK1를 감소시켜서 자가포식을 유도하였습니다. 집합적으로, AMPK를 표적화하는 것은 OR 세포의 화학적 내성을 극복하고 항암제에 대한 화학민감성을 회복시키는 솔루션을 제공할 수 있습니다. | - |
| dc.description.tableofcontents | I. INTRODUCTION 1 <br>II. MATERIALS AND METHODS 4 <br> A. Chemicals 4 <br> B. Cell culture and establishment of oxaliplatin resistant in CRC cells 4 <br> C. Cell proliferation assay 5 <br> D. Immunofluorescence analysis 5 <br> E. Protein isolation and immunoblot analysis 6 <br> F. Statistical analysis 6 <br>III. RESULTS 7 <br> A. Establishment of resistance to oxaliplatin in CRC cells 7 <br> B. Effects of oxaliplatin resistance on drug efflux pumps 9 <br> C. Effects of oxaliplatin resistance on the metabolism of glucose 11 <br> D. Effects of AMPK on autophagy 13 <br> E. Effects of AMPK on glucose metabolism 18 <br>IV. DISCUSSION 22 <br>V. CONCLUSION 26 <br>REFERENCES 28 <br>KOREAN ABSTRACT 33 | - |
| dc.language.iso | eng | - |
| dc.publisher | The Graduate School, Ajou University | - |
| dc.rights | 아주대학교 논문은 저작권에 의해 보호받습니다. | - |
| dc.title | Role of AMPK in regulation of oxaliplatin-resistant human colorectal cancer | - |
| dc.title.alternative | 인간 대장암의 옥살리플라틴 내성 조절에서 AMPK의 역할 연구 | - |
| dc.type | Thesis | - |
| dc.contributor.affiliation | 아주대학교 대학원 | - |
| dc.contributor.department | 일반대학원 바이오헬스규제과학과 | - |
| dc.date.awarded | 2023-02 | - |
| dc.description.degree | Master | - |
| dc.identifier.localId | T000000032499 | - |
| dc.identifier.url | https://dcoll.ajou.ac.kr/dcollection/common/orgView/000000032499 | - |
| dc.subject.keyword | AMPK | - |
| dc.subject.keyword | Akt-mTOR | - |
| dc.subject.keyword | autophagy | - |
| dc.subject.keyword | chemoresistance | - |
| dc.subject.keyword | colorectal cancer | - |
| dc.subject.keyword | glycolysis | - |
| dc.subject.keyword | oxaliplatin | - |
| dc.description.alternativeAbstract | Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In this study, oxaliplatin-resistant (OR) colorectal cancer (CRC) cells of HCT116, HT29, SW480, SW620 were stablished by gradually increasing the drug concentration to 2.5 μM. The inhibitory concentrations of cell growth by 50% (IC50) of oxaliplatin were 4.40–12.7-fold significantly higher in OR CRC cells as compared to their respective parental (PT) CRC cells. Phospho-Akt and phospho-mammalian target of rapamycin (mTOR) decreased in PT CRC cells but was overexpressed in OR CRC cells in response to oxaliplatin. In addition, an oxaliplatin-mediated decrease in phospho-AMP-activated protein kinase (AMPK) in PT CRC cells induced autophagy. Contrastingly, an increased phospho-AMPK in OR CRC cells was accompanied by a decrease in LC3B, further inducing the activity of glycolytic enzymes, such as glucose transporter 1 (GLUT1), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK1), to mediate cell survival. Inhibition of AMPK in OR CRC cells induced autophagy through inactivation of Akt/mTOR pathway and a decrease in GLUT1, PFKFB3 and PFK1. Collectively, targeting AMPK may provide solutions to overcome chemoresistance in OR CRC cells and restore chemosensitivity to anticancer drugs. | - |
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