NAPRT-mediated deamidated NAD biosynthesis enhances colon tissue resiliency and suppresses tumorigenesis

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Nicotinamide adenine dinucleotide (NAD) is crucial for cellular metabolism and is synthesized via salvage and de novo pathways.
• NAD-producing enzymes are often upregulated in cancer, contributing to rapid proliferation.
• The role of specific NAD synthesis pathways, like the deamidated pathway, in tumor suppression is not fully understood.

Purpose of the Study:

• To investigate the role of nicotinic acid phosphoribosyl transferase (NAPRT), a key enzyme in deamidated NAD biosynthesis, in tumorigenesis.
• To determine if physiological levels of NAPRT can suppress tumor development.
• To explore the therapeutic potential of boosting deamidated NAD biosynthesis for cancer prevention.

Main Methods:

• Utilized mouse models to study the effects of NAPRT deficiency on tumorigenesis and colitis.
• Assessed poly-(ADP-ribose) polymerases activity and DNA repair mechanisms in NAPRT-deficient cells.
• Correlated NAPRT expression levels with patient prognosis in various human cancer types.

Main Results:

• Physiological levels of NAPRT were found to suppress tumorigenesis, contrary to the oncogenic role of other NAD-producing enzymes.
• NAPRT is enriched in gut epithelial cells, supporting NAD homeostasis and stress response.
• NAPRT deficiency led to impaired DNA repair, increased sensitivity to colitis and chemically induced tumors, and spontaneous tumor development in aged mice.
• Low NAPRT expression correlated with poor prognosis in several human cancers.

Conclusions:

• Homeostatic levels of deamidated NAD biosynthesis, mediated by NAPRT, contribute to tumor suppression.
• NAPRT plays a critical role in maintaining genomic stability and preventing cancer development.
• Enhancing the NAPRT-mediated NAD synthesis pathway presents a potential strategy for cancer prevention and treatment.