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 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.

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

“…In some cases, NAMPT was found to be a direct transcriptional target of c-Myc, resulting in a positive feedback loop between c-Myc, NAMPT, and SIRT1 that drove tumor cell proliferation and progression (74)(75)(76). These studies showed that the use of NAMPT inhibitors resulted in a loss of SIRT1 expression, derepression of TP53, and decreased tumor cell growth in CRC models (74,75,77). A similar effect has been observed in prostate (19) and gastric cancer models (78).…”

“…Among these insights are an appreciation of the role of NAMPT in sirtuin expression (73). In CRC models, several groups have reported that regulation of SIRT1 activity is mediated by NAMPT (74)(75)(76)(77). In some cases, NAMPT was found to be a direct transcriptional target of c-Myc, resulting in a positive feedback loop between c-Myc, NAMPT, and SIRT1 that drove tumor cell proliferation and progression (74)(75)(76).…”

“…In CRC models, several groups have reported that regulation of SIRT1 activity is mediated by NAMPT (74)(75)(76)(77). In some cases, NAMPT was found to be a direct transcriptional target of c-Myc, resulting in a positive feedback loop between c-Myc, NAMPT, and SIRT1 that drove tumor cell proliferation and progression (74)(75)(76). These studies showed that the use of NAMPT inhibitors resulted in a loss of SIRT1 expression, derepression of TP53, and decreased tumor cell growth in CRC models (74,75,77).…”

Advances in NAD-Lowering Agents for Cancer Treatment

“…SIRT1, in turn, stabilizes c-MYC and enhances its transcriptional activity, and promotes tumorigenesis through the attenuation of p53 activity and the inhibition of c-MYC-induced apoptosis [ 38 ]. This c-MYC–NAMPT–SIRT1 positive feedback loop was found to be activated in colorectal carcinoma and its interruption was proposed as a viable therapeutic intervention [ 59 , 60 ]. Additionally, the high-mobility group A (HMGA1) protein was reported to be another protein regulating NAMPT expression through a different enhancer element [ 39 ].…”

Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration

“…One of the key stimulators of mitochondrial biogenesis is the c-myc oncogene, which activates the expression of genes that regulate the cycles of mitochondrial fusion and fission to expand the mitochondria content in the cell [ 96 ]. In actively proliferating cells, the expression of c-myc leads to the activation of the NAD+-synthesizing enzyme (NAMPT), an increase in the level of NAD+ and an increase in the activity of sirtuin 1 (NAD+-dependent histone deacetylase); thereby, mitotic activity and cell viability are preserved [ 97 ]. However, other evidence suggests that expression of c-myc causes an increase in glycolytic activity in proliferating cells and leads to a decrease in NAD + levels [ 98 ].…”