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(+)-Usnic acid modulates the Nrf2-ARE pathway in FaDu hypopharyngeal carcinoma cells
Violetta Krajka-Kuźniak1, Jarosław Paluszczak2, Robert Kleszcz2
1Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznan, Poland. vkrajka@ump.edu.pl.
Abstract:
Naturally occurring phytochemicals of different origin and structure, arctigenin, bergenin, usnic acid and xanthohumol, were shown to affect Nrf2 pathway in the context of various diseases, but their effect on this pathway in cancer cells was not extensively investigated. This study aimed to evaluate the effect of these compounds on Nrf2 expression and activation in hypopharyngeal FaDu squamous cell carcinoma cells. FaDu cells were treated with 2 or 10 μM arctigenin, bergenin, (+)-usnic acid or xanthohumol for 24 h. While arctigenin, bergenin, and xanthohumol did not affect either Nrf2 expression or activation, (+)-usnic acid treatment increased its transcript level and increased the nuclear/cytosol Nrf2 protein ratio-the measure of Nrf2 pathway activation. Consequently, (+)-usnic acid enhanced the transcription and translation of Nrf2 target genes: NQO1, SOD, and to a lesser extent, GSTP. The treatment of FaDu cells with (+)-usnic acid decreased both GSK-3β transcript and protein level, indicating its possible involvement in Nrf2 activation. All the tested compounds decreased Bax mRNA but did not change the level of Bax protein. (+)-Usnic acid tended to increase the percentage of early apoptotic cells and LC3 protein, autophagy marker. Significant induction of p53 also was observed after treatment with (+)-usnic acid. In summary, the results of this study indicate that low concentrations of (+)-usnic acid activate Nrf2 transcription factor, most probably as a result of ROS accumulation, but do not lead to FaDu hypopharyngeal carcinoma cells death.
Insights
(+)-Usnic acid activates the Nrf2 pathway in hypopharyngeal cancer cells, increasing protective gene expression. This phytochemical shows potential for cancer research but does not induce cell death at tested concentrations.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Naturally occurring phytochemicals like arctigenin, bergenin, usnic acid, and xanthohumol influence the Nrf2 pathway in various diseases.
- The impact of these phytochemicals on the Nrf2 pathway specifically within cancer cells remains under-investigated.
Purpose of the Study:
- To assess the effects of arctigenin, bergenin, (+)-usnic acid, and xanthohumol on Nrf2 expression and activation in FaDu hypopharyngeal squamous cell carcinoma cells.
- To explore the molecular mechanisms underlying any observed changes in Nrf2 pathway activity.
Main Methods:
- FaDu cells were exposed to 2 or 10 μM concentrations of the selected phytochemicals for 24 hours.
- Quantitative analysis of Nrf2 transcript levels, nuclear/cytosol Nrf2 protein ratio, and target gene expression (NQO1, SOD, GSTP) was performed.
- Changes in GSK-3β, Bax, p53, and LC3 protein levels were evaluated to understand pathway modulation and cellular effects.
Main Results:
- (+)-Usnic acid significantly upregulated Nrf2 transcript levels and increased the nuclear/cytosol Nrf2 protein ratio, indicating pathway activation.
- (+)-Usnic acid enhanced the expression of Nrf2 target genes (NQO1, SOD, GSTP) and decreased GSK-3β levels.
- While other compounds showed no effect on Nrf2, (+)-usnic acid also induced p53, increased LC3 protein, and tended to increase early apoptotic cells without causing significant cell death.
Conclusions:
- Low concentrations of (+)-usnic acid activate the Nrf2 transcription factor in FaDu hypopharyngeal carcinoma cells, likely via reactive oxygen species (ROS) accumulation.
- (+)-Usnic acid modulates key proteins involved in cell survival and apoptosis pathways, including GSK-3β, p53, and LC3.
- Despite activating the Nrf2 pathway and influencing apoptosis markers, (+)-usnic acid did not induce cell death in this cancer cell model at the tested concentrations.
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