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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
[Targeting NAD metabolism in neuroendocrine carcinoma]
1Miyagi Cancer Center Research Institute.
Abstract:
NAD is an important metabolite that functions as a cofactor in various metabolic reactions, and its biosynthesis is known to be upregulated during malignant transformation. The NAD salvage, in which NAMPT is a rate-limiting enzyme, is a predominant pathway for NAD synthesis in most tissues including cancer. However, less is known about how cancer sensitivity against NAMPT inhibition (NAMPTi) is dictated. Here we report that lung and prostate neuroendocrine carcinomas (NECs) are extremely vulnerable to NAMPTi and that the therapeutic effect of NAMPTi is markedly enhanced by dietary restriction of the NAD precursor, niacin. We found that de novo NAD synthesis is inactivated during neuroendocrine differentiation of tumor cells, leading to a high dependence of NEC cells on NAD salvage. Further investigations in mouse transplantation models showed that lowering blood levels of nicotinic acid riboside (NAR), one of the non-classical niacin, dramatically increases the therapeutic effect of NAMPTi on NEC. Metabolic studies showed that dietary nicotinic acid is converted to NAR and then released into the circulation, and NAD synthesis using NAR substrates can compensate for the effects of NAMPTi in tumor cells. These findings reveal that niacin restriction with NAMPTi is synthetic lethal to NECs.
Insights
Neuroendocrine carcinomas (NECs) are highly sensitive to NAMPT inhibition. Combining NAMPT inhibition with niacin restriction creates a synthetic lethal effect, offering a novel therapeutic strategy for NECs.
Area of Science:
- Biochemistry
- Metabolic pathways
- Cancer biology
Context:
- Nicotinamide adenine dinucleotide (NAD) is crucial for metabolic reactions and its biosynthesis is altered in cancer.
- The NAD salvage pathway, with NAMPT as the rate-limiting enzyme, is a primary NAD synthesis route in most tissues, including tumors.
- The determinants of cancer sensitivity to NAMPT inhibition are not fully understood.
Purpose:
- To investigate the vulnerability of neuroendocrine carcinomas (NECs) to NAMPT inhibition.
- To explore the impact of dietary NAD precursor restriction on NAMPT inhibition efficacy.
- To elucidate the underlying metabolic mechanisms driving NEC sensitivity.
Summary:
- Lung and prostate NECs exhibit extreme sensitivity to NAMPT inhibition.
- De novo NAD synthesis is suppressed during neuroendocrine differentiation, increasing NEC reliance on NAD salvage.
- Dietary restriction of niacin, a NAD precursor, significantly enhances the therapeutic effect of NAMPT inhibition in NECs.
- Nicotinic acid riboside (NAR), derived from dietary niacin, can compensate for NAMPT inhibition; lowering NAR levels potentiates NAMPTi efficacy.
- The combination of niacin restriction and NAMPT inhibition demonstrates a synthetic lethal interaction in NECs.
Impact:
- Reveals a critical metabolic vulnerability in NECs.
- Identifies a novel therapeutic strategy combining NAMPT inhibition with niacin restriction for NEC treatment.
- Provides a deeper understanding of NAD metabolism in neuroendocrine tumor progression and treatment response.
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