Colorectal cancer (CRC) refractory disease often relies on nicotinamide adenine dinucleotide(NAD)-dependent mechanisms. High levels of NAD confer therapy resistance to tumors. We report that NAMPT, the rate-limiting enzyme of physiological NAD biosynthesis, increases tumorigenic properties and induces cancer stem cell-like properties through pathways that control stem cell signaling. NAMPT inhibition increased the sensitivity to apoptosis in both NAMPT-expressing mature cells and

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... ng cell population. Therefore, NAMPT represents a novel therapeutic target in colon cancer progression and relapse, particularly targeting the CIC subset of human colon cancers. We also report a novel NAMPT-driven signature that stratify prognosis on CRC patients from high to low expression groups. NAMPT-driven signature may help to stratify patients unable to respond to classical chemotherapy to enroll on NAMPT inhibition trials or on other targeted treatments. Research. on July 9, 2020. SUMMARY Purpose: Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men worldwide. However, despite current progress, many patients with advanced and metastatic tumors still die from the malignancy. Refractory disease often relies on nicotinamide adenine dinucleotide(NAD)-dependent mechanisms. NAD metabolism and a stable NAD regeneration circuit are required to maintain tissue homeostasis and metabolism. However, high levels of NAD confer therapy resistance to tumors. Experimental Design: ectopic overexpression of nicotinamide phosphoribosil transferase (NAMPT) and shRNAs in CRC cell lines, Tumorigenic and stemness properties and transcription measurement in culture and in vivo. Transcriptional analisis in public databases. Therapeutic approaches. Results: NAMPT, the rate-limiting enzyme responsible for the highest source of physiological NAD biosynthesis, increases tumorigenic properties and induces cancer stem cell-like properties through pathways that control stem cell signaling, thus enriching the cancer-initiating cell (CIC) population. Furthermore, NAMPT expression correlated with high levels of CIC-like cells in colon tumors directly extracted from patients, and transcription meta-analysis revealed that NAMPT is also a key factor that induces cancer stem pathways in CRC tumors. This effect is mediated by PARP and SIRT1. Additionally, we report a novel NAMPT-driven signature that stratifies prognosis from high to low expression groups. The NAMPT signature contained SIRT1 and PARP1 levels as well as other CSC-related genes. Finally, NAMPT inhibition increased the sensitivity to apoptosis in both NAMPTexpressing cells and tumorspheres. Conclusions: NAMPT represents a novel therapeutic target in colon cancer progression and relapse, particularly the CIC subset of human colon cancers. Research. on July 9, 2020.