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.
Highlights
Gliomas are the most lethal and prevalent primary brain tumors in adults and are associated with a poor median survival time, which barely exceeds 12 months despite newly available treatments [1, 2]
We report that Nicotinamide phosphoribosyl transferase (NAMPT) overexpression in glioma cell lines increases tumorigenic properties controlling stem cell pathways and enriching the cancer-initiating cell (CIC) population
We found that NAMPT was highly overexpressed in glioblastoma tissue compared with healthy brain tissue (Figure 1B)
Summary
Gliomas are the most lethal and prevalent primary brain tumors in adults and are associated with a poor median survival time, which barely exceeds 12 months despite newly available treatments [1, 2]. These unsuccessful attempts to manage gliomas have stimulated research for more effective therapies. Tumor heterogeneity is partially explained by the cancer-initiating cell (CIC) hypothesis, which states that a cellular hierarchy exists in some tumors with selfrenewing CICs, generating the progeny that are responsible for tumor complexity [3, 4]. Targeting CICs offers a potential new treatment frontier for glioma control
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