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Apigenin enhances the cytotoxic effects of tumor necrosis factor-related apoptosis-inducing ligand in human rheumatoid arthritis fibroblast-like synoviocytes

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Abstract

Activated rheumatoid arthritis (RA) fibroblast-like synoviocytes (RAFLSs) play a central role in both initiating and driving RA. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been documented to induce apoptosis only in a small proportion of RAFLSs, which is followed by an induction of proliferation in surviving cells. Apigenin, a chemopreventive bioflavonoid, exhibits proapoptotic activity in many types of cells. In the present study, we sought to determine whether apigenin could enhance the cytotoxic effect of TRAIL on activated RAFLSs. Human RAFLSs isolated from patients with RA were treated with TRAIL (1 nM), apigenin (20 μM), or their combination, and subjected to apoptosis analysis after a 24-h incubation and proliferation analysis after a 72-h incubation. Apoptosis assay revealed that TRAIL or apigenin alone induced a marked apoptosis in RAFLS and their combination yielded a synergistic increase in RAFLS apoptosis. Immunoblotting analysis of apoptosis regulators demonstrated that combined treatment with apigenin increased caspase-3 expression and activity and decreased the Bcl-2/Bax ratio relative to treatment with TRAIL alone. The presence of apigenin significantly restrained TRAIL-induced RAFLS proliferation, coupled with restoration of the expression of two cell-cycle inhibitors p21 and p27. Moreover, the combination with apigenin blunted TRAIL-induced activation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. Our data collectively demonstrate that apigenin sensitizes RAFLS to TRAIL-induced apoptosis and counteracts TRAIL-dependent RAFLS proliferation, which is likely mediated through inactivation of PI3-K/Akt signaling pathway.

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Acknowledgment

This work was supported by the National Natural Science Foundation of China (31070747).

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Authors and Affiliations

  1. Central Laboratory of Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University Medical College, Shanghai, China

    Qing-wen Sun & Li Zhang

  2. State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China

    Song-min Jiang

  3. Department of Pathology, Shanghai Changhai Hospital Affiliated to Second Military University, Shanghai, China

    Ke Yang & Jian-ming Zheng

  4. Department of Orthopedics, Shanghai Changhai Hospital Affiliated to Second Military University, Shanghai, China

    Wei-dong Xu

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  1. Qing-wen Sun
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  2. Song-min Jiang
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  3. Ke Yang
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  4. Jian-ming Zheng
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  5. Li Zhang
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Correspondence to Qing-wen Sun or Wei-dong Xu.

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Qing-wen Sun and Song-min Jiang have contributed equally to this work.

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Sun, Qw., Jiang, Sm., Yang, K. et al. Apigenin enhances the cytotoxic effects of tumor necrosis factor-related apoptosis-inducing ligand in human rheumatoid arthritis fibroblast-like synoviocytes. Mol Biol Rep 39, 5529–5535 (2012). https://doi.org/10.1007/s11033-011-1356-3

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  • DOI: https://doi.org/10.1007/s11033-011-1356-3

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