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. 2021 May 22;10(6):1047.
doi: 10.3390/plants10061047.

Dehydroabietic Acid Is a Novel Survivin Inhibitor for Gastric Cancer

Won-Jin Kim  1   2 , Woong Kim  2 , Jang-Mi Bae  1   2 , Jungsoo Gim  1   2   3 , Seok-Jun Kim  1   2   3
Affiliations

Dehydroabietic Acid Is a Novel Survivin Inhibitor for Gastric Cancer

Won-Jin Kim et al. Plants (Basel). .

Abstract

Gastric cancer is a malignant tumor with a high incidence and mortality rate worldwide. Nevertheless, anticancer drugs that can be used for gastric cancer treatment are limited. Therefore, it is important to develop targeted anticancer drugs for the treatment of gastric cancer. Dehydroabietic acid (DAA) is a diterpene found in tree pine. Previous studies have demonstrated that DAA inhibits gastric cancer cell proliferation by inducing apoptosis. However, we did not know how DAA inhibits the proliferation of gastric cancer cells through apoptosis. In this study, we attempted to identify the genes that induce cell cycle arrest and cell death, as well as those which are altered by DAA treatment. DAA-regulated genes were screened using RNA-Seq and differentially expressed genes (DEGs) analysis in AGS cells. RNA-Seq analysis revealed that the expression of survivin, an apoptosis inhibitor, was significantly reduced by DAA treatment. We also confirmed that DAA decreased survivin expression by RT-PCR and Western blotting analysis. In addition, the ability of DAA to inhibit survivin was compared to that of YM-155, a known survivin inhibitor. DAA was found to have a stronger inhibitory effect in comparison with YM-155. DAA also caused an increase in cleaved caspase-3, an apoptosis-activating protein. In conclusion, DAA is a potential anticancer agent for gastric cancer that inhibits survivin expression.

Keywords: dehydroabietic acid; gastric cancer; survivin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
DAA inhibited the cell growth in gastric cancer cells. WST-8 assays were performed to detect the cell viability by DAA treatment for 24 and 48 h in six gastric cancer cell lines (AGS, MKN-28, YCC-2, SNU-216, SNU-601, and SNU-668). Data are presented as mean ± SEM (n = 5). The statistical analysis was carried out by two-way ANOVA, p < 0.0001.
Figure 2
Figure 2
DAA treatment in AGS cells regulated the expression of various genes. (A) RNA sequencing was performed on samples prepped from AGS cells that underwent DAA treatment for 48 h. Then, the results of analyzing gene annotation were calculated (upregulated genes: fold change > 1.5, downregulated genes: fold change < 1.5, DAA/DMSO). (B) The heatmap shows 33 upregulated genes and 33 downregulated genes showing significant differences in expression. (C) Results of RT-PCR on genes (24 of the 33 upregulated genes, 22 of the 33 downregulated genes) analyzed via a heatmap.
Figure 3
Figure 3
DAA specifically reduced the expression level of survivin. (A) Detection of mRNA and protein expression of survivin in AGS cells with 85 µM DAA treatment for 48 h using by RT-PCR and Western blotting. (B) The overexpression of survivin and the inhibitory effect of DAA were determined. Survivin was overexpressed in AGS cells using a plasmid system; survivin-overexpressing AGS cells were treated with 85 µM of DAA for 48 h.
Figure 4
Figure 4
DAA exhibited a better inhibitory effect than survivin inhibitor YM-155. (A) AGS cells were treated with 85 µM and 5 nM of DAA and YM-155 for 48 h, respectively, and the expression of survivin was determined by RT-PCR and Western blotting. (B) AGS cells were treated with 85 µM and 5 nM of DAA and YM-155 for 48 h, respectively. After annexin V/PI staining, flow cytometry was performed. Bar graph shows the rates of early-stage and late-stage apoptosis. (C) AGS cells were treated with DAA and YM-155 for 48 h. Apoptosis-related protein expression was confirmed through Western blotting.
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