Gallic acid induces apoptosis of lung fibroblasts via a reactive oxygen species-dependent ataxia telangiectasia mutated-p53 activation pathway.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disorder characterized by the activation of fibroblasts and the overproduction of extracellular matrix. Fibroblast resistance to apoptosis leads to increased fibrosis. Targeting fibroblasts with apoptotic agents represents a major therapeutic intervention for debilitating IPF. Gallic acid (3,4,5-trihydroxybenzoic acid), a naturally occurring plant phenol, has been reported to induce apoptosis in tumor cell lines and renal fibroblasts. However, the effects of gallic acid on lung fibroblasts have not been investigated. The aim of the present study is to determine the effects of gallic acid on primary cultured mouse fibroblasts. Our results showed that gallic acid induces the apoptotic death of fibroblasts via both intrinsic and extrinsic apoptotic pathways by the elevation of PUMA, Fas, and FasL protein levels. Moreover, intracellular reactive oxygen species (ROS) generation and 8-hydroxy-2'-deoxyguanosine production were observed in gallic acid-stimulated fibroblasts. Mechanistic studies showed that gallic acid induces early phosphorylation of p53(Ser18) and histone 2AX(Ser139) (H2AX) via ataxia telangiectasia mutated (ATM) activation in response to ROS-provoked DNA damage. When mouse lung fibroblasts were treated with caffeine, an ATM kinase inhibitor, the levels of p53, phosphorylated p53(Ser18), and cell death induced by gallic acid were significantly attenuated. Additionally, pretreatment with antioxidants drastically inhibited the gallic acid-induced 8-hydroxy-2'-deoxyguanosine (8-OH-dG) formation and phosphorylation of p53(Ser18) and ATM(Ser1981), as well as apoptosis. Our results provide the first evidence of the activation of ROS-dependent ATM/p53 signaling as a critical mechanism of gallic acid-induced cell death in primary cultured mouse lung fibroblasts.

• Authors: Cheng-Yen Chuang, Hsiang-Chun Liu, Li-Chen Wu, Chiu-Yuan Chen, Jinghua Tsai Chang, Shih-Lan Hsu
• Journal: Journal of agricultural and food chemistry (J Agric Food Chem) Vol. 58 Issue 5 Pg. 2943-51 (Mar 10 2010) ISSN: 1520-5118 [Electronic] United States
• PMID: 20151649 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• DNA-Binding Proteins
• Reactive Oxygen Species
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• Gallic Acid
• Ataxia Telangiectasia Mutated Proteins
• Atm protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Ataxia Telangiectasia Mutated Proteins
• Cell Cycle Proteins (metabolism)
• Cells, Cultured
• DNA Damage
• DNA-Binding Proteins (metabolism)
• Flow Cytometry
• Gallic Acid (pharmacology)
• Lung (cytology, drug effects, metabolism)
• Mice
• Protein Serine-Threonine Kinases (metabolism)
• Reactive Oxygen Species (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Tumor Suppressor Proteins (metabolism)