Concomitant Nrf2- and ATF4-activation by Carnosic Acid Cooperatively Induces Expression of Cytoprotective Genes

• Published in: International journal of molecular sciences Vol. 20; no. 7; p. 1706
• Main Authors: Mimura, Junsei, Inose-Maruyama, Atsushi, Taniuchi, Shusuke, Kosaka, Kunio, Yoshida, Hidemi, Yamazaki, Hiromi, Kasai, Shuya, Harada, Nobuhiko, Kaufman, Randal J, Oyadomari, Seiichi, Itoh, Ken
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05.04.2019; MDPI
• Subjects: Abietanes - pharmacology; Actinomycin; Activating transcription factor 4; Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Activation; Aldehyde Reductase - genetics; Aldehyde Reductase - metabolism; Aldo-Keto Reductases; antioxidant; Antioxidants; Antioxidants - metabolism; Astrocytes; ATF4; carnosic acid; Cell Line, Tumor; Cooperation; Cycloheximide; Cytoprotection - drug effects; Cytoprotection - genetics; Double-stranded RNA; eIF-2 kinase; Endoplasmic reticulum; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Heme; Homeostasis; Humans; Hydroquinones - pharmacology; Initiation factor eIF-2α; Kinases; Models, Biological; Nerve Growth Factor - genetics; Nerve Growth Factor - metabolism; Neurodegeneration; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NGF; Nrf2; Phosphorylation; Protein biosynthesis; Protein kinase; Protein synthesis; Proteins; Signal Transduction - drug effects; Stress response; Stress, Physiological - drug effects; Transcription; Transcription factors; Translation; Tumor cell lines; Tunicamycin - pharmacology; Antioxidant; NGF; Nrf2; Carnosic acid; ATF4
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20071706

Carnosic acid (CA) is a phytochemical found in some dietary herbs, such as L., and possesses antioxidative and anti-microbial properties. We previously demonstrated that CA functions as an activator of nuclear factor, erythroid 2 (NF-E2)-related factor 2 (Nrf2), an oxidative stress-responsive transcription factor in human and rodent cells. CA enhances the expression of nerve growth factor (NGF) and antioxidant genes, such as in an Nrf2-dependent manner in U373MG human astrocytoma cells. However, CA also induces gene expression in an Nrf2-independent manner, since 50 μM of CA administration showed striking gene induction compared with the classical Nrf2 inducer -butylhydroquinone (tBHQ) in U373MG cells. By comparative transcriptome analysis, we found that CA activates activating transcription factor 4 (ATF4) in addition to Nrf2 at high doses. CA activated ATF4 in phospho-eIF2α- and heme-regulated inhibitor kinase (HRI)-dependent manners, indicating that CA activates ATF4 through the integrated stress response (ISR) pathway. Furthermore, CA activated Nrf2 and ATF4 cooperatively enhanced the expression of and many antioxidant genes while acting independently to certain client genes. Taken together, these results represent a novel mechanism of CA-mediated gene regulation evoked by Nrf2 and ATF4 cooperation.