Cancer research (Chicago, Ill.), 2017-07, Vol.77 (14), p.3857-3869
2017
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- Autor(en) / Beteiligte
- Titel
- Nicotinic Acid Phosphoribosyltransferase Regulates Cancer Cell Metabolism, Susceptibility to NAMPT Inhibitors, and DNA Repair
- Ist Teil von
- Cancer research (Chicago, Ill.), 2017-07, Vol.77 (14), p.3857-3869
- Ort / Verlag
- United States: American Association for Cancer Research, Inc
- Erscheinungsjahr
- 2017
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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 and ; 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. .
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0008-5472eISSN: 1538-7445DOI: 10.1158/0008-5472.can-16-3079Titel-ID: cdi_proquest_miscellaneous_1899409509
- Format
- –
- Schlagworte
- Animals, Biosynthesis, BRCA2 protein, Breast cancer, Cell Line, Tumor, Cell size, Chemotherapy, Clinical trials, Cytokines - antagonists & inhibitors, Cytokines - genetics, Cytokines - metabolism, Deoxyribonucleic acid, DNA, DNA damage, DNA Repair, Energy balance, Enzyme Inhibitors - pharmacology, Enzymes, Female, Gene Amplification, Gene expression, HEK293 Cells, Heterografts, Humans, Inhibitors, Metabolism, Mice, Mice, Inbred BALB C, Mice, Nude, NAD, Nicotinamide, Nicotinamide phosphoribosyltransferase, Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors, Nicotinamide Phosphoribosyltransferase - genetics, Nicotinamide Phosphoribosyltransferase - metabolism, Nicotinic acid, Ovarian cancer, Ovarian carcinoma, Ovarian Neoplasms - drug therapy, Ovarian Neoplasms - enzymology, Ovarian Neoplasms - genetics, Pancreatic cancer, Phosphoribosyltransferase, Protein biosynthesis, Protein synthesis, Tumors, Xenograft Model Antitumor Assays