Nicotinic Acid Phosphoribosyltransferase Regulates Cancer Cell Metabolism, Susceptibility to NAMPT Inhibitors, and DNA Repair.
- Piacente F Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
- Caffa I Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
- Ravera S Department of Pharmacy, Biochemistry Lab, Genoa, Italy.
- Sociali G Department of Experimental Medicine, University of Genoa, Genoa, Italy.
- Passalacqua M Department of Experimental Medicine, University of Genoa, Genoa, Italy.
- Vellone VG Department of Integrated, Surgical and Diagnostic Sciences, University of Genoa, Genoa, Italy.
- Becherini P Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
- Reverberi D Ospedale Policlinico San Martino, I.R.C.C.S. per l'Oncologia, Genoa, Italy.
- Monacelli F Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
- Ballestrero A Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
- Odetti P Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
- Cagnetta A Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
- Cea M Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
- Nahimana A Service and Central Laboratory of Hematology, University Hospital of Lausanne, Lausanne, Switzerland.
- Duchosal M Service and Central Laboratory of Hematology, University Hospital of Lausanne, Lausanne, Switzerland.
- Bruzzone S Department of Experimental Medicine, University of Genoa, Genoa, Italy.
- Nencioni A Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy. alessio.nencioni@unige.it.
- 2017-05-17
Published in:
- Cancer research. - 2017
Animals
Cell Line, Tumor
Cytokines
DNA Repair
Enzyme Inhibitors
Female
Gene Amplification
HEK293 Cells
Heterografts
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Nicotinamide Phosphoribosyltransferase
Ovarian Neoplasms
Xenograft Model Antitumor Assays
English
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. Cancer Res; 77(14); 3857-69. ©2017 AACR.
- Language
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- English
- Open access status
- bronze
- Identifiers
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- DOI 10.1158/0008-5472.CAN-16-3079
- PMID 28507103
- Persistent URL
- https://folia.unifr.ch/global/documents/29226
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