대장암에서 AKT/mTOR 경로를 통한 옥살리플라틴 내성 발현에 관한 연구
Chemoresistance of oxaliplatin through AKT-mTOR pathway in colon cancers
- 주제(키워드) colon cancer , oxaliplatin , chemoresistance , AKT-mTOR , LC3B
- 발행기관 아주대학교
- 지도교수 김소희
- 발행년도 2020
- 학위수여년월 2020. 2
- 학위명 석사
- 학과 및 전공 일반대학원 약학과
- 실제URI http://www.dcollection.net/handler/ajou/000000029688
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Oxaliplatin is a third-generation platinum analog that can interfere with DNA replication and transcription by DNA damage. Continuous exposure of oxaliplatin resulted in resistance to oxaliplatin but no mechanisms of oxaliplatin-resistance were reported. In this study, oxaliplatin resistant cells were established using HCT116, HT29, SW480 and SW620 colon cancer cells by gradually increasing drug concentration up to a maximum of 2 µM at least for 3 month. The 50% inhibitory concentrations of cell growth (IC50) of oxaliplatin were 5.34, 9.88, 10.1 and 9.49-fold higher in oxaliplatin resistant HCT116, HT29, SW480, and SW620 cells, respectively, compared to their respective parental cells. One mechanism is that the expression of AKT and mTOR proteins were overexpressed in the oxaliplatin-resistant colon cancer cells. In addition, the expression of LC3B, an autophagy marker, decreased along with increasing AKT/mTOR signals, which caused the increase in glucose metabolism to produce energy for cell survival in oxaliplatin-resistant cancer cells. Taken together, oxaliplatin-resistance might be mediated through the activation of AKT/mTOR pathway in colon cancer cells, and AKT/mTOR might be a potential targets for oxaliplatin-resistance in human colon cancers.
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ABSTRACT i
TABLE OF CONTENTS ii
LIST OF FIGURES iv
LIST OF TABLES vi
ABBREVIATIONS vii
I. INTRODUCTION 1
II. MATERIALS AND METHOD 3
A. Chemicals 3
B. Cell culture and establishment of oxaliplatin-resistant cells 3
C. Cell proliferation assay 4
D. Flow cytometry analysis 4
E. Immunofluorescence analysis 5
F. Immunoblot analysis 5
G. Statistical analysis 6
III. RESULTS 7
A. Oxaliplatin-resistance of colon cancer cells 7
B. Drug efflux pump protein expression 10
C. Induction of cell cycle arrest by oxaliplatin 12
D. Protein expression on apoptosis and cell cycle 15
E. Induction of autophagy by oxaliplatin 17
F. Effect of oxaliplatin-resistance on AKT/mTOR pathway 19
G. Effect of oxaliplatin-resistance on glucose metabolism 21
IV. DISCUSSION 23
V. CONCLUSIONS 26
REFFERENCES 28
KOREAN ABSTRACT 33
