NAMPT Is a Potent Oncogene in Colon Cancer Progression that Modulates Cancer Stem Cell Properties and Resistance to Therapy through Sirt1 and PARP
| Autor: | Daniel Otero-Albiol, Sandra Muñoz-Galván, Amancio Carnero, Antonio Lucena-Cacace, Manuel P. Jiménez-García |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Colon Colorectal cancer Population Poly (ADP-Ribose) Polymerase-1 Datasets as Topic Mice Nude 03 medical and health sciences 0302 clinical medicine PARP1 Sirtuin 1 Cancer stem cell Cell Line Tumor medicine Animals Humans RNA Small Interfering Nicotinamide Phosphoribosyltransferase education Tissue homeostasis education.field_of_study Oncogene business.industry Gene Expression Profiling Oncogenes NAD Prognosis medicine.disease Survival Analysis Xenograft Model Antitumor Assays 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Colonic Neoplasms Neoplastic Stem Cells Cancer research Cytokines Female NAD+ kinase Stem cell business Signal Transduction |
| Zdroj: | Clinical Cancer Research. 24:1202-1215 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Colorectal cancer 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 colorectal cancer cell lines, tumorigenic and stemness properties and transcription measurement in culture and in vivo. Transcriptional analysis in public databases. Therapeutic approaches. Results: NAMPT, the rate-limiting enzyme responsible for the highest source of physiologic 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 colorectal cancer tumors. This effect is mediated by PARP and SIRT1. In addition, 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 cancer stem cell–related genes. Finally, NAMPT inhibition increased the sensitivity to apoptosis in both NAMPT-expressing cells and tumorspheres. Conclusions: NAMPT represents a novel therapeutic target in colon cancer progression and relapse, particularly the CIC subset of human colon cancers. Clin Cancer Res; 24(5); 1202–15. ©2017 AACR. |
| Databáze: | OpenAIRE |
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