COX-2 Inhibitor Contributes Cell Death in Rheumatoid Arthritis Fibroblast-like Synoviocytes Via PI3K/AKT/mTOR Signaling Pathway Triggered By Autophagy

Sang-Hyon Kim¹, Jihye Bang², Ji-Min Kim¹, Chang-Nam Son¹, Jin-Nyeong Chae¹ and Hye-Jin Jeong³, ¹Division of Rheumatology, Department of Internal Medicine, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Republic of Korea, Daegu, Korea, Republic of (South), ²Division of Rheumatology, Department of Internal Medicine, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea, Republic of (South), ³Department of Rheumatology, Keimyung University Dongsan Medical Center, Daegu, Korea, Republic of (South)

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: autophagy, COX inhibitors, fibroblasts and rheumatoid arthritis (RA)

Session Information

Date: Monday, November 6, 2017

Title: Rheumatoid Arthritis – Small Molecules, Biologics and Gene Therapy Poster II: Prognostic Factors, Imaging and Miscellaneous Reports

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Recently, the possibilities that autophagy regulates apoptosis resistance and hyperplasia of fibroblast-like synoviocytes (FLS) were also presented. The aim of this study is to investigate the influence of COX-2 inhibitor on viability of rheumatoid arthritis (RA) FLS and to reveal how COX-2 inhibitor affects the viability of RAFLS.

Methods: RA synovial tissue was obtained from patients during total knee replacement surgery or arthroscopy. FLS was cultured with COX-2 inhibitor, caspase inhibitor (z-VAD-fmk), autophagy inhibitor (3-methyladenine; 3-MA), knockdown of si-autophagy protein 5 (Atg5) or si-Beclin1. Cell viability was measured by MTS assay and by cell count using trypan blue staining. The expression of autophagy flux was analyzed by western blot and apoptosis activation was measured caspase3/7 activity assay.

Results: Synoviocyte from RA patients showed that COX-2 inhibitor attenuated cell proliferation and promoted apoptosis. A kind of COX-2 inhibitor dose-dependently decreased cell viability (IC50 of 120 μM) of RAFLS. COX-2 inhibitor also increased the expression of conversion of LC3-I to LC3-II, Atg5, Beclin1, p62 and decreased expression of lysosomal associated membrane protein 1 (LAMP1) in RAFLS. Combination of autophagy by 3-MA, si-Atg5 or si-Beclin1 restored viability of RAFLS by COX-2 inhibitor. COX-2 inhibitor decreased expression of phosphorylation-AKT signaling pathway. And, COX-2 inhibitor-induced autophagic cell death via ROS-dependent effect in RAFLS.

Conclusion: Taken together, this study indicated that COX-2 inhibitor induced apoptosis, inhibiting RA-FLS proliferation while promoting autophagic cell death by the PI3K/AKT/mTOR signaling pathway. Then, autophagy regulation may be an effective therapeutic strategy in inflammatory autoimmune disease such as RA.

Disclosure: S. H. Kim, None; J. Bang, None; J. M. Kim, None; C. N. Son, None; J. N. Chae, None; H. J. Jeong, None.

To cite this abstract in AMA style:

Kim SH, Bang J, Kim JM, Son CN, Chae JN, Jeong HJ. COX-2 Inhibitor Contributes Cell Death in Rheumatoid Arthritis Fibroblast-like Synoviocytes Via PI3K/AKT/mTOR Signaling Pathway Triggered By Autophagy [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/cox-2-inhibitor-contributes-cell-death-in-rheumatoid-arthritis-fibroblast-like-synoviocytes-via-pi3kaktmtor-signaling-pathway-triggered-by-autophagy/. Accessed .

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/cox-2-inhibitor-contributes-cell-death-in-rheumatoid-arthritis-fibroblast-like-synoviocytes-via-pi3kaktmtor-signaling-pathway-triggered-by-autophagy/