Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Apr 20:12:836257.
doi: 10.3389/fonc.2022.836257. eCollection 2022.

A Nicotinamide Phosphoribosyltransferase Inhibitor, FK866, Suppresses the Growth of Anaplastic Meningiomas and Inhibits Immune Checkpoint Expression by Regulating STAT1

Yuxuan Deng  1 , Boyi Hu  2 , Yazhou Miao  1 , Jing Wang  2 , Shaodong Zhang  2 , Hong Wan  2 , Zhen Wu  1 , Yifan Lv  1 , Jie Feng  2 , Nan Ji  1 , Deric Park  3 , Shuyu Hao  1
Affiliations

A Nicotinamide Phosphoribosyltransferase Inhibitor, FK866, Suppresses the Growth of Anaplastic Meningiomas and Inhibits Immune Checkpoint Expression by Regulating STAT1

Yuxuan Deng et al. Front Oncol. .

Abstract

Anaplastic meningioma is classified as a World Health Organization (WHO) grade III tumor and shows a strong tendency to recur. Although the incidence of anaplastic meningioma is low, the high rate of recurrence and death still makes treatment a challenge. A proteomics analysis was performed to investigate the differentially expressed proteins between anaplastic meningiomas and fibrous meningiomas by micro-LC-MS/MS. The key metabolic enzyme nicotinamide phosphoribosyltransferase (NAMPT) showed upregulated expression in anaplastic meningiomas. However, targeting NAMPT to treat anaplastic meningiomas has not been reported. In vitro, NAMPT inhibitor -FK866 reduced the viability of anaplastic meningiomas by inducing cell cycle arrest at the G2/M phase. Intriguingly, the NAMPT inhibitor -FK866 decreased the protein expression of immune checkpoints PD-L1 and B7-H3 by down-regulating the STAT1 and p-STAT1 expression in vitro. Furthermore, FK866 suppressed the growth of anaplastic meningiomas in an in vivo xenograft model. The expression of Ki-67 and immune checkpoint proteins (PD-L1 and B7-H3) showed significant differences between the group treated with FK866 and the control group treated with DMSO. In conclusion, the expression of NAMPT, which plays a crucial role in energy metabolism, was upregulated in anaplastic meningiomas. The NAMPT inhibitor -FK866 significantly suppressed the growth of anaplastic meningiomas in vitro and in vivo. More strikingly, FK866 potently inhibited immune checkpoint protein (PD-L1 and B7-H3) expression by regulating STAT1 in vitro and in vivo. Our results demonstrated that NAMPT inhibitors could potentially be an effective treatment method for patients suffering from anaplastic meningiomas.

Keywords: NAMPT; NAMPT inhibitor; anaplastic meningioma; cell cycle; immune checkpoint; proteomics.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The workflow of proteomic strategy.
Figure 2
Figure 2
(A) The twenty enriched biological processes according to GO analysis. Most of differentially expressed proteins are metabolite interconversion enzymes (PC00262). (B) The different functions of the metabolite interconversion enzymes (PC00262). Oxidoreductase (PC00176) and transferase (PC00220) enzymes accounts for more than half of the metabolic interconversion enzymes. (C) Diagram listing the transferases related to the differentially expressed proteins. The y-axis represents the fold change, and the x-axis lists the names of transferases. Red represents a high expression level in anaplastic meningiomas, while blue represents a low expression level.
Figure 3
Figure 3
(A) NAD is synthesized from tryptophan, nicotinic acid (NA) and nicotinamide (NM) through de novo, Preiss-Handler, and salvage pathways. (B, C) The relative expression of NAMPT (NAMPT/β-actin) in fibrous meningioma samples (n=6) and anaplastic meningiomas samples (n=3) was detected by Western blotting. (D, E) The expression of NAMPT in fibrous meningioma samples and anaplastic meningiomas samples was detected by immunohistochemical staining. FMs: fibrous meningiomas AMs: anaplastic meningiomas. **p < 0.01.
Figure 4
Figure 4
(A, B) Inhibitory effects of FK866 on IOMM cells as demonstrated using the CCK-8 assay. The cells were treated with various concentrations of FK866 (0–25 µM) for 24, 48 and 72 h. (C, D) The proliferation of IOMM cells treated with FK866 or DMSO was detected by colony formation assay. (E, F) Percentage of EdU positive cells among IOMM cells. **p < 0.01, ****p < 0.0001.
Figure 5
Figure 5
(A, B) Distribution of the cell cycle in IOMM cells treated with FK866 or DMSO. (C, D) Changes in NAMPT (NAMPT/GAPDH) and STAT1 (STAT1/GAPDH) mRNA relative expression in IOMM cells treated with FK866 or DMSO. (E, F) Changes in STAT1 (STAT1/β-actin) and p-STAT1 (p-STAT1/β-actin) protein relative expression in IOMM cells treated with FK866 or DMSO. (G, H) Changes in PD-L1 (PD-L1/β-actin) and B7-H3 (B7-H3/β-actin) protein relative expression in IOMM cells treated with FK866 or DMSO. *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 6
Figure 6
(A, B) Mice bearing IOMM meningiomas were treated with intraperitoneal injections of FK866 or DMSO on day 10, and the tumors were collected on day 25 (N=5/group).(C) The tumor volume at 3, 6, 9, 12 and 15 days after treatment. Tumor size (mm3) = [d2 x D]/2, d is the shortest diameter and D is the largest diameter. (D) The results of tumor weight analysis. (E, F) Immunohistochemical staining for Ki-67, PD-L1, B7-H3 in IOMM cell-derived meningiomas treated with DMSO and FK866. *p < 0.05, **p < 0.01, ****p < 0.0001.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Cao X, Hao S, Wu Z, Wang L, Jia G, Zhang L, et al. . Survival Rates, Prognostic Factors and Treatment of Anaplastic Meningiomas. J Clin Neurosci (2015) 22(5):828–33. doi: 10.1016/j.jocn.2014.11.022 - DOI - PubMed
    1. Yang SY, Park CK, Park SH, Kim DG, Chung YS, Jung HW. Atypical and Anaplastic Meningiomas: Prognostic Implications of Clinicopathological Features. J Neurol Neurosurg Psychiatry (2008) 79(5):574–80. doi: 10.1136/jnnp.2007.121582 - DOI - PubMed
    1. Sughrue ME, Sanai N, Shangari G, Parsa AT, Berger MS, McDermott MW. Outcome and Survival Following Primary and Repeat Surgery for World Health Organization Grade III Meningiomas. J Neurosurg (2010) 113(2):202–9. doi: 10.3171/2010.1.JNS091114 - DOI - PubMed
    1. Palma L, Celli P, Franco C, Cervoni L, Cantore G. Long-Term Prognosis for Atypical and Malignant Meningiomas: A Study of 71 Surgical Cases. J Neurosurg (1997) 86(5):793–800. doi: 10.3171/jns.1997.86.5.0793 - DOI - PubMed
    1. Goldbrunner R, Minniti G, Preusser M, Jenkinson MD, Sallabanda K, Houdart E, et al. . EANO Guidelines for the Diagnosis and Treatment of Meningiomas. Lancet Oncol (2016) 17(9):e383–91. doi: 10.1016/S1470-2045(16)30321-7 - DOI - PubMed