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김현석
김현석 (Hyun Seok Kim) 저자 이메일 보기
연세대학교 의과대학
 
조회 493  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
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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.
달콤한 대화의 진화 [Nat. Ecol. Evol.]
이대한
발표: 이대한 (Northwestern University)
일자: 2019년 12월 12일 (목) 오후 01시 (한국시간)
언어: 한국어
참석자 접수신청하기
수학울렁증에 대한 인지신경과학적 접근[Sci. Adv.]
최경환
발표: 최경환 (University of Chicago)
일자: 2019년 12월 19일 (목) 오후 02시 (한국시간)
언어: 한국어
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