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- Title
Activated NAD<sup>+</sup> biosynthesis pathway induces olaparib resistance in BRCA1 knockout pancreatic cancer cells.
- Authors
Sasaki, Yuka; Inouchi, Takuma; Nakatsuka, Ryusuke; Inoue, Amane; Masutani, Mitsuko; Nozaki, Tadashige
- Abstract
PARP inhibitors have been developed as anti-cancer agents based on synthetic lethality in homologous recombination deficient cancer cells. However, resistance to PARP inhibitors such as olaparib remains a problem in clinical use, and the mechanisms of resistance are not fully understood. To investigate mechanisms of PARP inhibitor resistance, we established a BRCA1 knockout clone derived from the pancreatic cancer MIA PaCa-2 cells, which we termed C1 cells, and subsequently isolated an olaparib-resistant C1/OLA cells. We then performed RNA-sequencing and pathway analysis on olaparib-treated C1 and C1/OLA cells. Our results revealed activation of cell signaling pathway related to NAD+ metabolism in the olaparib-resistant C1/OLA cells, with increased expression of genes encoding the NAD+ biosynthetic enzymes NAMPT and NMNAT2. Moreover, intracellular NAD+ levels were significantly higher in C1/OLA cells than in the non-olaparib-resistant C1 cells. Upregulation of intracellular NAD+ levels by the addition of nicotinamide also induced resistance to olaparib and talazoparib in C1 cells. Taken together, our findings suggest that upregulation of intracellular NAD+ is one of the factors underlying the acquisition of PARP inhibitor resistance.
- Subjects
PANCREATIC cancer; NICOTINAMIDE; BRCA genes; OLAPARIB; CANCER cells; HOMOLOGOUS recombination; NAD (Coenzyme)
- Publication
PLoS ONE, 2024, Vol 19, Issue 4, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0302130