Blocking of JB6 Cell Transformation by Tanshinone IIA: Epigenetic Reactivation of Nrf2 Antioxidative Stress Pathway
Journal Title: The AAPS Journal - Year 2014, Vol 16, Issue 6
Abstract
Increasing numbers of natural products have been found to possess anticancer effects. Nuclear factor erythroid-2-related factor-2 (Nrf2) is a master regulator of the antioxidative stress response, and our previous studies found that epigenetic modification of the Nrf2 gene appears to be a critical mechanism. Salvia miltiorrhiza, a Chinese herbal medicine widely used in Asian countries, has been shown to possess anticancer and antioxidant effects. Tanshinone IIA (TIIA), an active component in S. miltiorrhiza, has been reported to activate Nrf2 pathway. The objective of this study was to investigate the epigenetic regulation of Nrf2 by TIIA in mouse skin epidermal JB6 cells and the functional consequences for cell transformation. TIIA was found to induce antioxidant response element-luciferase and upregulate the mRNA and protein levels of Nrf2 and Nrf2 downstream target genes HO-1 and NQO-1. TIIA decreased the colony formation of JB6 cells by approximately 80%. TIIA decreased the protein levels of DNMT1, DNMT3a, DNMT3b, and HDAC3 and inhibited the enzymatic activity of HDACs. Bisulfite genomic sequencing indicated that TIIA demethylated the first five CpGs in the promoter region of the Nrf2 gene. Chromatin immunoprecipitation assays showed that TIIA treatment increased the recruitment of RNA polymerase II at Nrf2 transcription start site but had limited effects on enrichment of Ac-H3 in Nrf2 promoter. Taken together, our results show that TIIA activates the Nrf2 signaling pathway and induces epigenetic demethylation of the CpGs of Nrf2. The epigenetic reactivation of the Nrf2 signaling pathway by TIIA could potentially contribute to the attenuation of JB6 cellular transformation and anticancer effects.
Authors and Affiliations
Ling Wang, Chengyue Zhang, Yue Guo, Zheng-Yuan Su, Yuqing Yang, Limin Shu, Ah-Ng Tony Kong
Keywords
Related Articles
- EP ID EP681729
- DOI 10.1208/s12248-014-9666-8
- Views 68
- Downloads 0
Impact of Anti-Drug Antibodies in Preclinical Pharmacokinetic Assessment
The administration of human biotherapeutics is often associated with a higher incidence of immunogenicity in preclinical species. The presence of anti-drug antibodies (ADAs) in the test samples can affect the accurate me...
Genotyping and drug response: Use of single nucleotide polymorphisms (SNPs) versus haplotypes to predict albuterol efficacy
Pharmacodynamic Model of Hepcidin Regulation of Iron Homeostasis in Cynomolgus Monkeys
The online version of this article (doi:10.1208/s12248-016-9886-1) contains supplementary material, which is available to authorized users.
Mathematical Model Approach to Describe Tumour Response in Mice After Vaccine Administration and its Applicability to Immune-Stimulatory Cytokine-Based Strategies
The online version of this article (doi:10.1208/s12248-013-9483-5) contains supplementary material, which is available to authorized users.
Targeted pharmaceutical nanocarriers for cancer therapy and imaging
The use of various pharmaceutical nanocarriers has become one of the most important areas of nanomedicine. Ideally, such carriers should be specifically delivered (targeted) to the pathological area to provide the maximu...