The c-MYC/NAMPT/SIRT1 feedback loop is activated in early classical and serrated route colorectal cancer and represents a therapeutic target

Journal Article · Tue Jan 15 04:00:00 EST 2019 · Medical Oncology (Online)

DOI:https://doi.org/10.1007/S12032-018-1225-1· OSTI ID:22938458

Brandl, Lydia ^[1]; Kirstein, Nina ^[2]; Neumann, Jens; Sendelhofert, Andrea ^[1]; Vieth, Michael ^[3]; Kirchner, Thomas ^[1]; Menssen, Antje ^[2]

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1. Ludwig-Maximilians University (LMU), Department of Pathology (Germany)
2. Research group “Signaling pathways in colorectal cancer”, Department of Pathology, Ludwig-Maximilians University (LMU) (Germany)
3. Klinikum Bayreuth, Department of Pathology (Germany)

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{sup +} 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.

• OSTI ID: 22938458
• Journal Information: Medical Oncology (Online), Journal Name: Medical Oncology (Online) Journal Issue: 1 Vol. 36; ISSN 1559-131X
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
ADENOMAS
CARCINOGENESIS
MAMMARY GLANDS
NICOTINAMIDE
PROTEINS
SENSITIVITY