NAMPT overexpression induces cancer stemness and defines a novel tumor signature for glioma prognosis

// Antonio Lucena-Cacace 1, 2 , Daniel Otero-Albiol 1, 2 , Manuel P. Jimenez-Garcia 1, 2 , Javier Peinado-Serrano 1 and Amancio Carnero 1, 2 1 Instituto de Biomedicina de Sevilla, IBIS, Hospital Universitario Virgen del Rocio, Universidad de Sevilla, Consejo Superior de Investigaciones Cientificas, Sevilla, Spain 2 CIBER DE CANCER, Instituto de Salud Carlos III, Madrid, Spain Correspondence to: Amancio Carnero, email: acarnero-ibis@us.es Keywords: NAMPT, cancer initiating cell, gene signature, glioma, glioblastoma Received: June 22, 2017      Accepted: July 25, 2017      Published: August 28, 2017 ABSTRACT Gliomas are the most prevalent primary malignant brain tumors associated with poor prognosis. NAMPT, a rate-limiting enzyme that boosts the nicotinamide adenine dinucleotide (NAD) regeneration in the salvage pathway, is commonly expressed in these tumors. NAD metabolism is required to maintain tissue homeostasis. To maintain metabolism, cancer cells require a stable NAD regeneration circuit. However, high levels of NAD confer resistance to therapy to these tumors, usually treated with Temozolomide (TMZ). We report that NAMPT overexpression in glioma cell lines increases tumorigenic properties controlling stem cell pathways and enriching the cancer-initiating cell (CIC) population. Furthermore, NAMPT expression correlated with high levels of Nanog, CD133 and CIC-like cells in glioblastoma directly extracted from patients. Meta-analysis reveals that NAMPT is also a key factor inducing cancer stem pathways in glioma cells. Furthermore, we report a novel NAMPT-driven signature which stratify prognosis within tumor staging. NAMPT signature also correlates directly with EGFR positive and IDH negative tumors. Finally, NAMPT inhibition increases sensitivity to apoptosis in both NAMPT-expressing cells and tumorspheres. Therefore, NAMPT represents a novel therapeutic target in Glioma progression and relapse.