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폐암에서 clobetasol propionate의 NRF2 억제효과 연구
- Alternative Title
- The mechanism of NRF2 inhibition by clobetasol propionate in lung cancer cells
- Author(s)
- 정병진
- Alternative Author(s)
- Byung-Jin Jung
- Advisor
- 전상민
- Department
- 일반대학원 약학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2018-02
- Language
- eng
- Abstract
- Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor E2-related factor 2 (NRF2) pathway는 세포의 항 산화 작용에 중요한 역할을 한다. KEAP1의 돌연변이에 의해 야기되는 NRF2의 활성화는 폐암에서 종종 발생한다. 국가암정보센터의 보고에 따르면, 폐암은 사망률 1위이며 5년 생존율은 췌장에 이어 2위인 질병이다. 그럼에도 불구하고 현재까지 발견된 효과적인 치료제는 없는 실정이다. 따라서 본 연구자는 효과적인 NRF2 억제제를 찾는 것이 폐암 치료를 위해 좋은 전략임을 시사한다. 지금까지 많은 NRF2 억제제가 발견되었지만 효과적이지 않았다. 따라서 본 연구자는 항암 전략으로서 clobetasol propionate (CP)에 의한 NRF2 억제의 메커니즘을 연구했다. 폐암에서 CP, NRF2 억제가 gluticorticoid receptor (GCR), glycogen synthase kinase 3 (GSK3), β-TrCP를 통해 NRF2의 proteasomal degradation을 촉진한다는 사실을 발견했다. 또한 CP는 NRF2를 핵에서 세포질로의 유출을 유도한다. 따라서 CP는 NRF2 proteasomal degradation을 유발하고 이에 따라 좋은 폐암 치료제로서 사용될 수 있다.
- Alternative Abstract
- The Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor E2-related factor 2 (NRF2) pathway plays an important role in antioxidant defense of cells. Activation of NRF2 caused by mutations in the KEAP1 often occurs in lung cancer. According to the National Cancer Information Center, lung cancer has the highest mortality rate and the 5-year survival rate is the second. Despite this fact, no effective therapeutic agent for lung cancer has been developed. Therefore, we suggest that inhibiting NRF2 is a good therapeutic strategy for lung cancer treatment. NRF2 inhibitors have been found, but they are not effective. We suggested that treatment of clobetasol propionate (CP) as a NRF2 inhibitors promotes the β-TrCP dependent degradation of NRF2 in Glucocorticoid receptor (GCR) and glycogen synthase kinase 3 (GSK3) dependent manner. We found the mechanism of NRF2 inhibition by CP as a potential anti-cancer strategy. We also showed that CP treatment leads to nuclear localization of NRF2. Thus we suggest that the CP leads to NRF2 proteasomal degradation.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Pharmacy > 3. Theses(Master)
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