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김현석(의생명과학부) Gastroenterology
등록일 : 2018-06-18 오후 12:16:00       조회 : 124
첨   부 :
제1저자 이주영 김효실(의생명과학부)
교신저자 김현석(의생명과학부, BK21) 정재호(외과학교실)

Gastroenterology. 2018 May 15. pii: S0016-5085(18)34544-X. doi: 10.1053/j.gastro.2018.05.024. [Epub ahead of print]
Selective Cytotoxicity of the NAMPT Inhibitor FK866 Toward Gastric Cancer Cells with Markers of the Epithelial-Mesenchymal Transition, Due to Loss of NAPRT.
Lee J1, Kim H1, Lee JE2, Shin SJ3, Oh S4, Kwon S5, Kim H4, Choi YY2, White MA6, Paik S1, Cheong JH7, Kim HS8.
Author information
1Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea.2Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea; Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea.3Department of Pathology, Hanyang University College of Medicine, Seoul, Korea.4Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea; Brain Korea 21 plus project for medical science, Yonsei University College of Medicine, Seoul 03722, Korea.5Graduate Program for Nanomedical Science, Yonsei University, Seoul 03722, Korea.6Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.7Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea; Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea; Brain Korea 21 plus project for medical science, Yonsei University College of Medicine, Seoul 03722, Korea. Electronic address: jhcheong@yuhs.ac.8Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea; Brain Korea 21 plus project for medical science, Yonsei University College of Medicine, Seoul 03722, Korea. Electronic address: hsfkim@yuhs.ac.

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.
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