Figure S7 from Nicotinic Acid Phosphoribosyltransferase Regulates Cancer Cell Metabolism, Susceptibility to NAMPT Inhibitors, and DNA Repair

Piacente, Francesco; Caffa, Irene; Ravera, Silvia; Sociali, Giovanna; Passalacqua, Mario; Vellone, Valerio G.; Becherini, Pamela; Reverberi, Daniele; Monacelli, Fiammetta; Ballestrero, Alberto; Odetti, Patrizio; Cagnetta, Antonia; Cea, Michele; Nahimana, Aimable; Duchosal, Michel; Bruzzone, Santina; Nencioni, Alessio

doi:10.1158/0008-5472.22414988.v1

00085472can163079-sup-174461_2_unknown_upload_4029638_mpqj4m.pdf (193.66 kB)

Figure S7 from Nicotinic Acid Phosphoribosyltransferase Regulates Cancer Cell Metabolism, Susceptibility to NAMPT Inhibitors, and DNA Repair

journal contribution

posted on 2023-03-31, 00:47 authored by Francesco Piacente, Irene Caffa, Silvia Ravera, Giovanna Sociali, Mario Passalacqua, Valerio G. Vellone, Pamela Becherini, Daniele Reverberi, Fiammetta Monacelli, Alberto Ballestrero, Patrizio Odetti, Antonia Cagnetta, Michele Cea, Aimable Nahimana, Michel Duchosal, Santina Bruzzone, Alessio Nencioni

Figure S7 shows that 2-hydroxynicotinate sodium salt (2-HNANa) effectively sensitizes OVCAR-5 cells to FK866.

Funding

Associazione Italiana per la Ricerca sul Cancro

Seventh Framework Program projects PANACREAS

ATHERO-B-CELL

Fondazione Umberto Veronesi

Italian Ministry of Health

5 × 1000 2014 Funds

IBSA Foundation

University of Genoa

History

ARTICLE ABSTRACT

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.