[DEBUG-WINDOW 처리영역 보기]
즐겨찾기  |  뉴스레터  |  오늘의 정보  |  e브릭몰e브릭몰 회원가입   로그인
BRIC홈 한국을 빛내는 사람들
물리적 거리두기 실천
스폰서배너광고 안내  배너1 배너2 배너3 배너4
LABox-과학으로 본 코로나19 (COVID-19)
전체보기 추천논문 상위피인용논문 인터뷰 그이후 한빛사통계
김현석
김현석 (Hyun Seok Kim) 저자 이메일 보기
연세대학교 의과대학
저자CV 보기
98 KB
 
조회 547  인쇄하기 주소복사 트위터 공유 페이스북 공유 
Selective Cytotoxicity of the NAMPT Inhibitor FK866 Toward Gastric Cancer Cells with Markers of the Epithelial–Mesenchymal Transition, Due to Loss of NAPRT
열기 Authors and Affiliations

Abstract
Background & Aims
Markers of the epithelial-mesenchymal transition (EMT) in gastric tumor tissues are associated with poor outcomes of patients. We performed a screen to identify pharmacologic compounds that kill gastric cancer cells with EMT-associated gene expression patterns and investigate their mechanisms.

Methods
We identified 29 gastric cancer cell lines with gene expression signature previously associated with an EMT subtype, based on data from RNA sequence analyses, and confirmed their mesenchymal phenotypes of 7 lines (Hs746T, SNU1750, MKN1, SK4, SNU484, SNU668, and YCC11), based in invasive activity and protein markers. We screened 1345 compounds for their ability to kill cells with the EMT signature, compared to cell lines without this pattern. We tested the effects of identified compounds in BALB/c nude mice bearing GA077 tumors; mice were given intraperitoneal injections of the compound or vehicle (control) twice daily for 24 days and tumor growth was monitored. Proteins associated with compounds’ toxicity were overexpressed in MKN1 and SNU484 cells, or knocked down in MKN45 and SNU719 using small interfering RNAs. We performed immunohistochemical analyses of 942 gastric cancer tissues and investigated associations between EMT markers and protein expression patterns.

Results
The nicotinamide phosphoribosyltransferase (NAMPT) inhibitor FK866 killed 6 of 7 gastric cancer cell lines with EMT-associated gene expression signatures but not gastric cancer cells without this signature. The 6 EMT-subtype gastric cell lines expressed significantly low levels of nicotinic acid phosphoribosyltransferase (NAPRT), which makes the cells hypersensitive to NAMPT inhibition. Gastric cell lines that expressed higher levels of NAPRT, regardless of EMT markers, were sensitized to FK866 after knockdown of NAPRT, whereas overexpression of NAPRT in deficient EMT cell lines protected them from FK866-mediated toxicity. Administration of FK866 to nude mice with tumors grown from GA077 cells (human gastric cancer tumors of the EMT subtype) led to tumor regression in 2 weeks; FK866 did not affect tumors grown from MKN45 cells without the EMT expression signature. Loss of NAPRT might promote the EMT, because it stabilizes beta-catenin. We correlated the EMT gene expression signature with reduced levels of NAPRT in 942 gastric tumors from patients; we also found reduced levels of NAPRT mRNA in colorectal, pancreatic, and lung adenocarcinoma tissues with the EMT gene-expression signature.

Conclusions
FK866 selectively kills gastric cancer cells with an EMT gene expression signature by inhibiting NAMPT in cells with NAPRT deficiency. Loss of NAPRT expression, frequently via promoter hypermethylation, is observed in many gastric tumors of the EMT subtype. FK866 might be used to treat patients with tumors of this subtype.

Key Words: stomach cancer, drug screen, partial EMT, synthetic lethal
논문정보
- 형식: Research article
- 게재일: 2018년 05월 (BRIC 등록일 2018-05-16)
- 연구진: 국내(교신)+국외 연구진태극기
- 분야: Cancer Biology/Oncology, Cell_Biology, Molecular_Biology
관련 보도자료
국내 연구진이 난치성 위암으로 불리는 상피중간엽전이(epithelial-mesenchymal transition, EMT) 분자아형 위암에서 표적 항암물질을 발견, 치료제 개발에 탄력을 받을 전망이다.
세포 형광 이미징 멀티플렉싱을 위한 초고속 사이클링[Angew. Chem.-Int. Edit.]
고진아
발표: 고진아 (Massachusetts General Ho...)
일자: 2020년 4월 14일 (화) 오전 10시 (한국시간)
언어: 영어
참석자 접수신청하기
The presenting symptoms of cancer and stage at diagnosis[Lancet Oncol.]
구민정
발표: 구민정 (University College Londo...)
일자: 2020년 4월 20일 (월) 오후 04시 (한국시간)
언어: 영어
참석자 접수신청하기

  댓글 0
등록
 
목록
(주)비아이코퍼레이션
관련링크
김현석 님 전체논문보기 >
관련인물
김효실 (연세대학교 의과대학)
이재은 (연세대학교 의과대학)
이주영 (연세대학교 의과대학)
정재호 (연세대학교 의과대학)
관련분야 논문보기
Cancer Biology/Oncology

Cell_Biology

Biochemistry

외부링크
Google (by Hyun Seok Kim)
Pubmed (by Hyun Seok Kim)
프리미엄 Bio일정 Bio일정 프리미엄 안내
[BRIC Webinar]The presenting symptoms of cancer and stage at diagnosis[Lancet Oncol.]
[BRIC Webinar]The presenting symptoms of cancer and stage at diagnosis[Lancet Oncol.]
사전접수: ~2020.04.20
날짜: 2020.04.20
Online 개최
[BRIC Webinar]세포 형광 이미징 멀티플렉싱을 위한 초고속 사이클링[Angew. Chem.-Int. Edit.]
[재직자무료교육] 분석기기(HPLC) 활용 품질검사 실습(4.9~4.10) / 화장품 제형제조 기술 실습(4.13~4.14)
[재직자무료교육] 분석기기(HPLC) 활용 품질검사 실습(4.9~4.10) / 화장품 제형제조 기술 실습(4.13~4.14)
날짜: 2020.04.09~14
장소: 충청북도 청주시 흥덕구 오송읍 오송생명1로 194-41 충북산학융합본부 기업연구1관 교육장
위로가기
한빛사 홈  |  한빛사FAQ  |  한빛사 문의 및 제안
 |  BRIC소개  |  이용안내  |  이용약관  |  개인정보처리방침  |  이메일무단수집거부
Copyright © BRIC. All rights reserved.  |  문의 member@ibric.org
트위터 트위터    페이스북 페이스북   유튜브 유튜브    RSS서비스 RSS
머크