期刊
DNA REPAIR
卷 23, 期 -, 页码 79-87出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.dnarep.2014.08.006
关键词
NAMPT; NAD(+) salvage pathway; Integrins; alpha v beta 3; Breast cancer; Metastasis
资金
- NIH [R01CA170737, R01CA170140, UL1RR025774]
- CDMRP DoD grant [BC123479]
- California Breast Cancer Research Program [17NB-0058, 16IB-0052, 12NB-0176, 18NB-0022]
- Susan G. Komen Foundation [KG101199]
- NATIONAL CANCER INSTITUTE [R01CA170737, R01CA170140] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [UL1RR025774] Funding Source: NIH RePORTER
NAD(+) metabolism is an essential regulator of cellular redox reactions, energy pathways, and a substrate provider for NAD(+) consuming enzymes. We recently demonstrated that enhancement of NAD(+)/NADH levels in breast cancer cells with impaired mitochondrial NADH dehydrogenase activity, through augmentation of complex I or by supplementing tumor cell nutrients with NAD(+) precursors, inhibits tumorigenicity and metastasis. To more fully understand how aberrantly low NAD(+) levels promote tumor cell dissemination, we here asked whether inhibition of NAD(+) salvage pathway activity by reduction in nicotinamide phosphoribosyltransferase (NAMPT) expression can impact metastasis and tumor cell adhesive functions. We show that knockdown of NAMPT, the enzyme catalyzing the rate-limiting step of the NAJD(+) salvage pathway, enhances metastatic aggressiveness in human breast cancer cells and involves modulation of integrin expression and function. Reduction in NAMPT expression is associated with upregulation of select adhesion receptors, particularly alpha v beta 3 and beta 1 integrins, and results in increased breast cancer cell attachment to extracellular matrix proteins, a key function in tumor cell dissemination. Interestingly, NAMPT downregulation prompts expression of integrin alpha v beta 3 in a high affinity conformation, known to promote tumor cell adhesive interactions during hematogenous metastasis. NAMPT has been selected as a therapeutic target for cancer therapy based on the essential functions of this enzyme in NAD(+) metabolism, cellular redox, DNA repair and energy pathways. Notably, our results indicate that incomplete inhibition of NAMPT, which impedes NAD(+) metabolism but does not kill a tumor cell can alter its phenotype to be more aggressive and metastatic. This phenomenon could promote cancer recurrence, even if NAMPT inhibition initially reduces tumor growth. (C) 2014 Elsevier B.V. All rights reserved.
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