期刊
CANCER RESEARCH
卷 77, 期 14, 页码 3857-3869出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-16-3079
关键词
-
类别
资金
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [6108, 17736]
- Seventh Framework Program [256986]
- ATHERO-B-CELL [602114]
- Fondazione Umberto Veronesi
- Italian Ministry of Health [GR-201102347192]
- IBSA Foundation
- University of Genoa
In the last decade, substantial efforts have been made to identify NAD(+) biosynthesis inhibitors, specifically against nicotinamide phosphoribosyltransferase (NAMPT), as preclinical studies indicate their potential efficacy as cancer drugs. However, the clinical activity of NAMPT inhibitors has proven limited, suggesting that alternative NAD(+) production routes exploited by tumors confer resistance. Here, we show the gene encoding nicotinic acid phosphoribosyltransferase (NAPRT), a second NAD(+)-producing enzyme, is amplified and overexpressed in a subset of common types of cancer, including ovarian cancer, where NAPRT expression correlates with a BRCAness gene expression signature. Both NAPRT and NAMPT increased intracellular NAD(+) levels. NAPRT silencing reduced energy status, protein synthesis, and cell size in ovarian and pancreatic cancer cells. NAPRT silencing sensitized cells to NAMPT inhibitors both in vitro and in vivo; similar results were obtained with the NAPRT inhibitor 2-hydroxynicotinic acid. Reducing NAPRT levels in a BRCA2-deficient cancer cell line exacerbated DNA damage in response to chemotherapeutics. In conclusion, NAPRT-dependent NAD(+) biosynthesis contributes to cell metabolism and to the DNA repair process in a subset of tumors. This knowledge could be used to increase the efficacy of NAMPT inhibitors and chemotherapy.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据