Targeting c-MYC through Interference with NAMPT and SIRT1 and Their Association to Oncogenic Drivers in Murine Serrated Intestinal Tumorigenesis

• Published in: Neoplasia (New York, N.Y.) Vol. 21; no. 10; pp. 974 - 988
• Main Authors: Brandl, Lydia, Zhang, Yina, Kirstein, Nina, Sendelhofert, Andrea, Boos, Sophie Luise, Jung, Peter, Greten, Florian, Rad, Roland, Menssen, Antje
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2019; Elsevier
• Subjects: Animals; Apoptosis - genetics; Biomarkers; Biopsy; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Cytokines - metabolism; Drug Resistance, Neoplasm - genetics; Immunohistochemistry; Intestinal Neoplasms - drug therapy; Intestinal Neoplasms - etiology; Intestinal Neoplasms - metabolism; Intestinal Neoplasms - pathology; Mice; Mutation; Neoplasm Metastasis; Nicotinamide Phosphoribosyltransferase - metabolism; Oncogenes; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins c-myc - metabolism; Signal Transduction; Sirtuin 1 - antagonists & inhibitors; Sirtuin 1 - metabolism; FOXO; mSA-HGD; MSI; mSH; mSA-LGD; IHC; PDTO; HTOM; MSS; PARP-1; SIRT1; CCAR2; DBC1; PI3K; CRC; FFPE; PBEF; NAMPT; PI; mSA
• ISSN: 1476-5586; 1476-5586
• DOI: 10.1016/j.neo.2019.07.009

We recently described a positive feedback loop connecting c-MYC, NAMPT, DBC1 and SIRT1 that contributes to unrestricted cancer cell proliferation. Here we determine the relevance of the loop for serrated route intestinal tumorigenesis using genetically well-defined BrafV600E and K-rasG12D mouse models. In both models we show that c-MYC and SIRT1 protein expression increased through progression from hyperplasia to invasive carcinomas and metastases. It correlated with high NAMPT expression and was directly associated to activation of the oncogenic drivers. Assessing functional and molecular consequences of pharmacological interference with factors of the loop, we found that inhibition of NAMPT resulted in apoptosis and reduced clonogenic growth in human BRAF-mutant colorectal cancer cell lines and patient-derived tumoroids. Blocking SIRT1 activity was only effective when combined with a PI3K inhibitor, whereas the latter antagonized the effects of NAMPT inhibition. Interfering with the positive feedback loop was associated with down-regulation of c-MYC and temporary de-repression of TP53, explaining the anti-proliferative and pro-apoptotic effects. In conclusion we show that the c-MYC-NAMPT-DBC1-SIRT1 positive feedback loop contributes to murine serrated tumor progression. Targeting the feedback loop exerted a unique, dual therapeutic effect of oncoprotein inhibition and tumor suppressor activation. It may therefore represent a promissing target for serrated colorectal cancer, and presumably for other cancer types with deregulated c-MYC.