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The regulatory mechanism of 4-phenylbutyric acid against ER stress-induced autophagy in human gingival fibroblasts

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Abstract

Endoplasmic reticulum (ER) stress is closely connected to autophagy. When cells are exposed to ER stress, cells exhibit enhanced protein degradation and form autophagosomes. In this study, we demonstrate that the chemical chaperone, 4-phenylbutyric acid (4-PBA), regulates ER stressinduced cell death and autophagy in human gingival fibroblasts. We found that 4-PBA protected cells against thapsigargin-induced apoptotic cell death but did not affect the reduced cell proliferation. ER stress induced by thapsigargin was alleviated by 4-PBA through the regulation of several ER stress-inducible, unfolded protein response related proteins including GRP78, GRP94, C/EBP homologous protein, phospho-eIF-2α, eIF-2α, phospho-JNK1 (p46) and phospho-JNK2/3 (p54), JNK1, IRE-1α, PERK, and sXBP-1. Compared with cells treated with thapsigargin alone, cells treated with both 4-PBA and thapsigargin showed lower levels of Beclin-1, LC-3II and autophagic vacuoles, indicating that 4-PBA also inhibited autophagy induced by ER stress. This study suggests that 4-PBA may be a potential therapeutic agent against ER stress-associated pathologic situations.

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Authors and Affiliations

  1. Department of Pharmacology and Institute of Cardiovascular Research, School of Medicine, Chonbuk National University, Jeonju, Chonbuk, 561-180, Korea

    Do-Sung Kim, Bo Li & Han-Jung Chae

  2. College of Pharmacy, Dongduk Women’ University, Seoul, 136-714, Korea

    Ki Yon Rhew

  3. Department of Public Oral Health and Preventive Dentistry, School of Dentistry, Wonkwang University, Iksan, Chonbuk, 570-749, Korea

    Hyo-Won Oh

  4. Department of Oral Medicine and Diagnosis, School of Dentistry, Wonkwang University, Iksan, Chonbuk, 570-749, Korea

    Hyun-Dae Lim

  5. Department of Oral and Maxillofacial Radiology, School of Dentistry, Wonkwang University, Iksan, Chonbuk, 570-749, Korea

    Wan Lee

  6. Department of Dental Pharmacology and Wonkwang Biomaterial Implant Research Institute, School of Dentistry, Wonkwang University, Iksan, Chonbuk, 570-749, Korea

    Hyung-Ryong Kim

  7. Department of Dental Pharmacology and Wonkwang Dental Research Institute, School of Dentistry, Wonkwang University, Iksan, Chonbuk, 570-749, Korea

    Hyung-Ryong Kim

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  1. Do-Sung Kim
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  2. Bo Li
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  5. Hyun-Dae Lim
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  6. Wan Lee
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  8. Hyung-Ryong Kim
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Correspondence to Han-Jung Chae or Hyung-Ryong Kim.

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Kim, DS., Li, B., Rhew, K.Y. et al. The regulatory mechanism of 4-phenylbutyric acid against ER stress-induced autophagy in human gingival fibroblasts. Arch. Pharm. Res. 35, 1269–1278 (2012). https://doi.org/10.1007/s12272-012-0718-2

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