초록

Ⅳ. 연구개발결과
1. 후박의 암 세포주기 저해하는 후보물질 탐색 및 조절물질의 발굴
2. 후보물질의 표적 단백질 저해 확인 및 작용 기전 기반 바이오마커 발굴
3. 후박성분의 암 생성/전이 관련 작용 생리 활성 기전 및 효능 연구
4. 후보물질의 표적 단백질 확인 및 효능검증
5. 후보물질을 통한 암 진단 바이오 마커 개발
6. 세포주기 조절 인자의 활성 저해, 효능검증 및 작용기전 확립을 통하여 산업계의 기술이전
을 목표로 후보물질의 대량 생산법 확립 및 유도체 선별 기술 확립

Abstract ▼

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality worldwide. Few effective therapeutic options for HCC are currently available and its prognosis is poor. Identification and clinical relevance of the major effectors and their roles in the tumor progression are esse

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality worldwide. Few effective therapeutic options for HCC are currently available and its prognosis is poor. Identification and clinical relevance of the major effectors and their roles in the tumor progression are essential to develop therapeutic targets and biomarkers for prognosis in HCC. We found that high VRK1 expression was significantly associated with poor prognosis of HCC patients and promoted HCC through regulating cell cycle-related effectors. VRK1 knockdown inhibited the proliferation of HCC, both in vitro and in vivo, through the G1 arrest. Treatment with luteolin, a VRK1 inhibitor, led to suppression of HCC cell proliferation. Our data suggest that VRK1 should serve as a potential therapeutic target for the treatment as well as a prognostic marker of HCC.
Targeting specific molecules is a promising cancer treatment because certain types of cancer cells are dependent on specific oncogenes. This strategy led to the development of therapeutics that use monoclonal antibodies or small-molecule inhibitors. However, the continued development of novel molecular targeting inhibitors is required to target the various oncogenes associated with the diverse types and stages of cancer. Obtusilactone B is a butanolide derivative purified from Machilus thunbergii. In this study, we show that obtusilactone B functions as a small-molecule inhibitor that causes abnormal nuclear envelope dynamics and inhibits growth by suppressing vaccinia-related kinase 1 (VRK1)-mediated phosphorylation of barrier-to-autointegration factor (BAF). BAF is important in maintaining lamin integrity, which is closely associated with diseases that include cancer. Specific binding of obtusilactone B to BAF suppressed VRK1-mediated BAF phosphorylation and the subsequent dissociation of the nuclear envelope from DNA that allows cells to progress through the cell cycle. Obtusilactone B potently induced tumor cell death in vitro, indicating that specific targeting of BAF to block cell cycle progression can be an effective anticancer strategy. Our results demonstrate that targeting a major constituent of the nuclear envelope may be a novel and promising alternative approach to cancer treatment.