Rottlerin induces cyclooxygenase-2 upregulation through an ATF4 and reactive oxygen species-independent pathway in HEI-OC1 cells

Woo,Seon  Min; Lee,Woo  Keun; Min,Kyoung‑Jin; Kim,Dong  Eun; Park,Soon  Hyung; Nam,Sung  Il; Kwon,Taeg  Kyu

doi:10.3892/mmr.2016.5320

Rottlerin induces cyclooxygenase-2 upregulation through an ATF4 and reactive oxygen species-independent pathway in HEI-OC1 cells

Authors:
- Seon Min Woo
- Woo Keun Lee
- Kyoung‑Jin Min
- Dong Eun Kim
- Soon Hyung Park
- Sung Il Nam
- Taeg Kyu Kwon
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Affiliations: Department of Immunology, School of Medicine, Keimyung University, Daegu 700712, Republic of Korea, Department of Otolaryngology, School of Medicine, Keimyung University, Daegu 700712, Republic of Korea
Published online on: May 20, 2016 https://doi.org/10.3892/mmr.2016.5320
Pages: 845-850

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Abstract

Hearing loss can be caused by infection, inflammation, loud noise and ototoxic drugs. The induction of cyclooxygenase-2 (COX‑2) expression is an important event during the cellular inflammatory response. The present study investigated the effect of rottlerin on CO-2 mRNA and protein expression in HEI-OC1 cells. Cell viability was determined using an MTT assay. Western blotting was used to examine the expression of COX‑2, endoplasmic reticulum stress-associated transcription factors and activation of the MAPK pathway. ROS was measured using the fluorescent probe 2', 7'-dichlorodihydrofluorescein diacetate. Treatment with the natural protein kinase C δ inhibitor, rottlerin, was shown to increase COX‑2 expression at the protein and mRNA levels in a dose‑dependent manner. Rottlerin was shown to induce increased reactive oxygen species (ROS) generation, however, ROS were not critical for rottlerin‑induced upregulation of COX‑2 expression in HEI‑OC1 cells. In addition, rottlerin was shown to increase the phosphorylation of p38 mitogen-activated protein kinase (MAPK). The pharmacological inhibition of p38MAPK and suppression of activating transcription factor 4 (an ER stress‑associated transcription factor) expression by small interfering RNA inhibited rottlerin-induced COX‑2 upregulation. Furthermore, COX‑2 expression levels were increased further when cells were treated with rottlerin and interleukin‑1β or protein kinase C activator, PMA. In conclusion, the results of the present study demonstrated that rottlerin is a novel inducer of COX‑2 expression and identified the mechanisms involved in this process. Rottlerin may be considered a potential activator of repair and remodeling.

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