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. 2017 Oct 24;9(1):718-725.
doi: 10.18632/oncotarget.22002. eCollection 2018 Jan 2.

Chemopreventative celecoxib fails to prevent schwannoma formation or sensorineural hearing loss in genetically engineered murine model of neurofibromatosis type 2

Benjamin M Wahle  1   2 , Eric T Hawley  1 , Yongzheng He  1 , Abbi E Smith  1 , Jin Yuan  1 , Andi R Masters  3 , David R Jones  3 , Jeffrey R Gehlhausen  1 , Su-Jung Park  1 , Simon J Conway  1 , D Wade Clapp  1 , Charles W Yates  1   2
Affiliations

Chemopreventative celecoxib fails to prevent schwannoma formation or sensorineural hearing loss in genetically engineered murine model of neurofibromatosis type 2

Benjamin M Wahle et al. Oncotarget. .

Abstract

Mutations in the tumor suppressor gene NF2 lead to Neurofibromatosis type 2 (NF2), a tumor predisposition syndrome characterized by the development of schwannomas, including bilateral vestibular schwannomas with complete penetrance. Recent work has implicated the importance of COX-2 in schwannoma growth. Using a genetically engineered murine model of NF2, we demonstrate that selective inhibition of COX-2 with celecoxib fails to prevent the spontaneous development of schwannomas or sensorineural hearing loss in vivo, despite elevated expression levels of COX-2 in Nf2-deficient tumor tissue. These results suggest that COX-2 is nonessential to schwannomagenesis and that the proposed tumor suppressive effects of NSAIDs on schwannomas may occur through COX-2 independent mechanisms.

Keywords: cyclooxygenase 2; neurofibromatosis type 2; non-steroidal anti-inflammatory agents; transgenic mice; vestibular schwannoma.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no potential conflicts of interest.

Figures

Figure 1
Figure 1. COX-2 is increased in Nf2-deficient mouse model of neurofibromatosis type 2
(A) Western blot analysis of COX-2 and Merlin in whole tissue lysate of tumor-forming trigeminal ganglia tissue of 6-month old Nf2f/f;PostnCre- or Nf2f/f;PostnCre+ mice. (B) Relative PTGS2 gene expression in trigeminal ganglia tissue of 6-8 month old Nf2f/f;PostnCre- or Nf2f/f;PostnCre+ mice by qPCR. (** P=.004).
Figure 2
Figure 2. Chemopreventative celecoxib treatment of Nf2-deficient mice
HPLC-MS/MS analysis of celecoxib levels in (A) plasma and (B) DRG tissue between treated and untreated mice. (*P <.05) (C) Mice were fed vehicle or celecoxib infused chow for 5 days followed by an IP injection of 100ng of LPS for induction of COX-2. Mice were sacrificed 2 hours post injection. Y axis measures COX-2 activity in units/mL of tissue lysate (P= 0.0379, unpaired t-test). (D) Mouse body weights of treated and untreated Nf2f/f;PostnCre+ mice.
Figure 3
Figure 3. Celecoxib fails to prevent schwannomagenesis or SNHL in Nf2-deficient mice
(A) DRG enlargement – Representative images of gross DRG enlargement between a Nf2f/f;PostnCre- mouse (left), vehicle and celecoxib-treated Nf2f/f;PostnCre+ mice (center and right) are shown (scale bar = 5 mm). Below, DRG volume is shown for the same groups of mice (ns = not significant; P >.05). (B) DRG histology – Schwannomas at later and earlier stages of development are shown for both vehicle and celecoxib-treated mice. (C) ABR – Thresholds are shown per ear for Nf2f/f;PostnCre-, vehicle and celecoxib-treated Nf2f/f;PostnCre+ mice.
See this image and copyright information in PMC

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