Abstract B158: Transcriptional profile of NAMPTi unveils modulation of Tankyrase and Wnt/B-catenin pathway.

The coenzyme, NAD, is as an essential redox factor in cellular biochemical processes such as respiration and metabolism. NAD is also a substrate for cellular enzymes including sirtuins and poly (ADP ribose) polymerases. NAMPT, which catalyzes the rate limiting step of NAD biosynthesis, has been considered as promising cancer target for more than a decade. NAMPT inhibitors profoundly inhibit tumor cell growth; however, the mechanism that leads to the tumor cell growth inhibition is not understood. In this work, we report the results of our exploration of the metabolic and transcriptional alterations post-NAMPT inhibition in HCT116 cell line. Our results show that NAMPTi induces a time-dependent modulation of tumor metabolism which in turn induces the reprogramming of tumor cell transcriptome concomitant with cell growth inhibition. The transcriptional profile revealed different metabolic and oncogenic signaling pathways are modulated by NAMPT inhibition. The wnt/b-catenin pathway was highlighted as one of the most modulated pathways by NAMPTi. We indeed confirmed that the NAMPTi induces the inhibition of b-catenin/TCF reporter system transfected in HCT116 cells or in HEK293 cells constitutively expressing Wnt3A. NAMPT inhibition induces a strong decrease of cyclinD1 and c-myc expression in agreement with the modulation of Wnt/b-catenin pathways. The NAMPTi impact on Wnt/b-catenin pathways can be seen in CRC cell lines bearing APC wt or APC mut and in cell lines with heterozygote but not homozygote b-catenin mutation suggesting that the effect of NAMPTi effect is upstream b-catenin. Our studies highlighted two potential mechanisms that contribute to wnt/b-catenin pathway modulation by NAMPTi. First, we observed an inhibition of disheveled activation and secondly, a decrease in the activity of tankyrase. The results obtained from these studies highlight the key role of NAMPT in tumor metabolism and the wnt/b-catenin oncogenic pathway. This suggests that modulation of wnt /b-catenin contributes to the antitumor activity of NAMPTi. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B158. Citation Format: Maysoun Shomali, Patrick McGlynn, Dmitri Wiederchain, Paul August, Francisco Adrian, Carlos Garcia-Echeverria, Joachim Theilhaber, Monsif Bouaboula. Transcriptional profile of NAMPTi unveils modulation of Tankyrase and Wnt/B-catenin pathway. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B158.