The c-MYC/NAMPT/SIRT1 feedback loop is activated in early classical and serrated route colorectal cancer and represents a therapeutic target.
Med Oncol
; 36(1): 5, 2018 Nov 20.
Article
em En
| MEDLINE
| ID: mdl-30460421
ABSTRACT
We have recently identified a positive feedback loop in which c-MYC increases silent information regulator 1 (SIRT1) protein level and activity through transcriptional activation of nicotinamide phosphoribosyltransferase (NAMPT) and NAD+ increase. Here, we determined the relevance of the c-MYC-NAMPT-SIRT1 feedback loop, including the SIRT1 inhibitor deleted in breast cancer 1 (DBC1), for the development of conventional and serrated colorectal adenomas. Immunohistochemical analyses of 104 conventional adenomas with low- and high-grade dysplasia and of 157 serrated lesions revealed that elevated expression of c-MYC, NAMPT, and SIRT1 characterized all conventional and serrated adenomas, whereas DBC1 was not differentially regulated. Analyzing publicly available pharmacogenomic databases from 43 colorectal cancer cell lines demonstrated that responsiveness towards a NAMPT inhibitor was significantly associated with alterations in PTEN and TGFBR2, while features such as BRAF or RNF43 alterations, or microsatellite instability typical for serrated route colorectal cancer, showed increased sensitivities for inhibition of NAMPT and SIRT1. Our findings suggest an activation of the c-MYC-NAMPT-SIRT1 feedback loop that may crucially contribute to initiation and development of both routes to colorectal cancer. Targeting of NAMPT or SIRT1 may represent novel therapeutic strategies with putative higher sensitivity of the serrated route colorectal cancer subtype.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
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Adenoma
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Citocinas
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Proteínas Proto-Oncogênicas c-myc
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Nicotinamida Fosforribosiltransferase
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Sirtuína 1
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Med Oncol
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Alemanha