NAMPT Is a Potent Oncogene in Colon Cancer Progression that Modulates Cancer Stem Cell Properties and Resistance to Therapy through Sirt1 and PARP
Antonio Lucena-Cacace,Antonio Lucena-Cacace,Daniel Otero-Albiol,Daniel Otero-Albiol,Manuel P. Jiménez-García,Manuel P. Jiménez-García,Sandra Muñoz-Galván,Sandra Muñoz-Galván,Amancio Carnero,Amancio Carnero +9 more
TLDR
NAMPT represents a novel therapeutic target in colon cancer progression and relapse, particularly the CIC subset of human colon cancers, and a novel NAMPT-driven signature that stratifies prognosis from high to low expression groups is reported.Abstract:
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.read more
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Journal ArticleDOI
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential.
Na Xie,Lu Zhang,Wei Gao,Canhua Huang,Canhua Huang,Peter E. Huber,Xiaobo Zhou,Changlong Li,Guobo Shen,Bingwen Zou,Bingwen Zou +10 more
TL;DR: Recent advances in the understanding of the molecular mechanisms of NAD -regulated physiological responses to stresses, the contribution of NAD + deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention are summarized.
Journal ArticleDOI
NAD Metabolism in Cancer Therapeutics.
TL;DR: NAD metabolism is implicated in cancer pathogenesis beyond energy metabolism and considered a promising therapeutic target for cancer treatment, and recent findings with respect to NAD metabolism are presented.
Journal ArticleDOI
NAD+ metabolism, stemness, the immune response, and cancer.
Lola E. Navas,Amancio Carnero +1 more
TL;DR: In this article, the role of NAD+ and NAMPT in the ways that they may influence cancer metabolism, the immune system, stemness, aging, and cancer is reviewed, and some ongoing research on therapeutic approaches.
Journal ArticleDOI
NAD+ Metabolism Maintains Inducible PD-L1 Expression to Drive Tumor Immune Evasion
Hongwei Lv,Guishuai Lv,Guishuai Lv,Chen Ci'an,Zong Qianni,Guoqing Jiang,Dan Ye,Xiuliang Cui,Yufei He,Xiang Wei,Qin Han,Liang Tang,Wen Yang,Hongyang Wang +13 more
TL;DR: NAMPT, the rate-limiting enzyme of the NAD+ biogenesis, drives interferon γ-induced PD-L1 expression in multiple types of tumors and governs tumor immune evasion in a CD8+ T cell-dependent manner, and NAD+ replenishment combined with PD-(L)1 antibody provides a promising therapeutic strategy for immunotherapy-resistant tumors.
Journal ArticleDOI
Targeting cancer stem cells and their niche: perspectives for future therapeutic targets and strategies
Yue Zhao,Qiongzhu Dong,Jiahui Li,Kai-Li Zhang,Jie Qin,Jiangang Zhao,Qiye Sun,Zhefang Wang,Thomas Wartmann,Karl-Walter Jauch,Peter J. Nelson,Lun-Xiu Qin,Christiane Bruns +12 more
TL;DR: It is hoped that new strategies and related therapeutic approaches as outlined here may help prevent the formation of the metastatic niche, as well as counter tumor progression and metastatic growth.
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