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Role of AMPK in regulation of oxaliplatin-resistant human colorectal cancer
- Alternative Title
- 인간 대장암의 옥살리플라틴 내성 조절에서 AMPK의 역할 연구
- Author(s)
- 정예서
- Advisor
- 김소희
- Department
- 일반대학원 바이오헬스규제과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2023-02
- Language
- eng
- Keyword
- AMPK; Akt-mTOR; autophagy; chemoresistance; colorectal cancer; glycolysis; oxaliplatin
- 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.
- Alternative Abstract
- 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.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Biohealth Regulatory Science > 3. Theses(Master)
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