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

ABSTRACT: 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 Braf^V600E and K-ras^G12D 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 col

SUBMITTER: Brandl L 

PROVIDER: S-EPMC6710297 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature