Emodin Inhibits EBV Reactivation and Represses NPC Tumorigenesis
<p>Epstein-Barr virus (EBV) positive nasopharyngeal carcinoma (NPC) cells are more resistant to emodin. (<b>a</b>) The chemical structure of emodin. (<b>b</b>) NPC cell lines (TW01, HONE-1) and their EBV infected counterparts (NA, HA) were treated with indicated concentrations of emodin for 48 h, followed by cell viability assay and CC50 calculation (top of each panel). The values are means ± SD from at least three independent experiments. (* <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001 compared to the group of 0 μM).</p> "> Figure 2
<p>The expression of EBV lytic proteins in epithelial cell lines is inhibited by emodin. Western blot analysis of EBV positive NA (<b>a</b>) and HA (<b>b</b>) cells treated with emodin alone (left panels) or emodin and TPA+SB (right panels). Zta, Rta, EAD, DNase are EBV lytic proteins, GAPDH serves as a loading control. Forty ng/mL TPA, 3 mM SB, and 1 to 50 μM emodin were used in this experiment.</p> "> Figure 3
<p>The amount of EAD-positive cells is decreased by emodin treatment of EBV-positive epithelial cell lines. (<b>a</b>,<b>b</b>) immunofluorescence assay of NA (<b>a</b>) and HA (<b>b</b>) cells exposed to indicated concentrations of emodin one hour before TPA+SB induction (TPA+SB 24 h). EBV diffusive early antigen (EAD) serves as a surrogate marker for virus reactivation (red). Scale bar: 100 μm. (<b>c</b>,<b>d</b>) Flow cytometry analysis was used to quantitate EAD positive cells in each treatment as denoted in (<b>a</b>,<b>b</b>). TS, TPA + SB; E, emodin.</p> "> Figure 4
<p>Virus production is inhibited by emodin treatment. EBV virions released in the culture media of NA (<b>a</b>) and HA (<b>b</b>) cells treated with TPA + SB (TS) or TS plus emodin (TS + E1, TS + E10, TS + E20, TS + E50) were collected, treated with DNase I to remove free DNA present in the media. Viral genome was purified by proteinase K digestion and subjected to qPCR analysis of EBV DNA polymerase gene fragment (BALF5). Untreated cells served as spontaneous lytic replication control (Mock). Data are means ± SD of two independent experiments. (* <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001 compared to the TS group).</p> "> Figure 5
<p>The activities of Zp and Rp are repressed by emodin treatment of NA cells. (<b>a</b>,<b>b</b>) NA and its parental EBV negative cell line, TW01, were transfected with luciferase reporters containing Zp or Rp, followed by emodin (E) and TPA + SB (TS) treatments. After TS induction for 24 h, cell lysates were collected for measurement of luciferase activity. Data are means ± SD from at least two independent experiments. (<b>c</b>,<b>d</b>) Zta-expressing plasmid (Z) was co-transfected with Zp or Rp luciferase reporters into NA (<b>c</b>) or TW01 (<b>d</b>) cells, with same emodin and TPA+SB treatments depicted in (<b>a</b>,<b>b</b>). (<b>e</b>,<b>f</b>) same to (<b>c</b>,<b>d</b>), except Rta-expressing plasmid (R) was used. (* <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001 compared to the groups of TS, Z or R, respectively).</p> "> Figure 5 Cont.
<p>The activities of Zp and Rp are repressed by emodin treatment of NA cells. (<b>a</b>,<b>b</b>) NA and its parental EBV negative cell line, TW01, were transfected with luciferase reporters containing Zp or Rp, followed by emodin (E) and TPA + SB (TS) treatments. After TS induction for 24 h, cell lysates were collected for measurement of luciferase activity. Data are means ± SD from at least two independent experiments. (<b>c</b>,<b>d</b>) Zta-expressing plasmid (Z) was co-transfected with Zp or Rp luciferase reporters into NA (<b>c</b>) or TW01 (<b>d</b>) cells, with same emodin and TPA+SB treatments depicted in (<b>a</b>,<b>b</b>). (<b>e</b>,<b>f</b>) same to (<b>c</b>,<b>d</b>), except Rta-expressing plasmid (R) was used. (* <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001 compared to the groups of TS, Z or R, respectively).</p> "> Figure 6
<p>Z1D and ZII domains of Zp are important for emodin inhibition. (<b>a</b>) Luciferase activities of TW01 cells harboring wild type Zp (spanning −221 to +1 region, top) or serial 5’-deletion mutants (Zp-184, −167, −134, −99, −80, −51). Three hours after transfection, the cells were pre-treated with emodin for 1 h followed by TPA+SB treatment for an additional 24 h. The relative folds of luciferase activities are means ± SD from three independent experiments. (<b>b</b>) Luciferase activities of emodin/TPA+SB-treated TW01 cells harboring wild type Zp and mutants of cellular factor binding sites located in the Z1D and ZII domains (mZ1D-1, mZ1D-2, ZII-1, ZII-2). The relevant mutated sites are represented by a black triangle (▲). (<b>c</b>) The SP1 and β-actin of NA cells were detected after EBV induction with emodin treatment for 24 h. (<b>d</b>) NA cells were co-transfected with Zp reporter and vector or SP1-expressing plasmid for 3 h, respectively. After transfection, the cells were pretreated with emodin and activated EBV with TPA+SB. After 24 h of incubation, the luciferase activities were detected. Values are means ± SD from three independent experiments. (* <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001 compared to the group of TS).</p> "> Figure 7
<p>Emodin represses reactivation-induced tumorigenic properties. The EBV-positive cell line NA was treated with TPA+SB repeatedly to investigate various tumorigenic properties. (<b>a</b>) For detection of MN formation, the cells were harvested after 10 repeated treatments with TPA+SB, with or without emodin, and stained with DAPI for MN examination using fluorescence microscopy. (<b>b</b>) For detection of cell proliferation, the cells were subjected to WST-1 assay after 10 repeated treatments with TPA+SB, with or without emodin, to detect the cell proliferation over the following 3 days. For cell migration (<b>c</b>) and cell invasion (<b>d</b>) assays, repeated TPA+SB induced NA cells were subjected to Oris system (c) or HTS FluoroBlock transwell (d) in the presence or absence of emodin, followed by cell counts. Scale bar: 100 μm. Data are the mean ± SD from three independent experiments. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01.</p> "> Figure 8
<p>Emodin represses the tumor growth in a mouse model. NA cells were prepared for subcutaneous inoculation into severe combined immunodeficient (SCID) mice, which then received various treatments. (<b>a</b>) The diagram presents the schedule for in vivo assay of EBV reactivation inhibited by emodin. (<b>b</b>) The average animal body weights during the experiment were measured (<span class="html-italic">n</span> = 6 mice for each group). (<b>c</b>) The diameters of tumor nodules were monitored weekly using calipers throughout the experiment. (<b>d</b>) The tumor weights were measured after the mice were sacrificed. Tumor nodules were photographed as the listed pictures. Data are presented as mean ± SD. * <span class="html-italic">p</span> < 0.05.</p> ">
Abstract
:1. Introduction
2. Results
2.1. The Cytotoxicity of Emodin to the NPC Cell Lines
2.2. Emodin Inhibits EBV Lytic Protein Expression in NPC Cells
2.3. The Inhibition of Virion Production by Emodin
2.4. The Repression of Zta Promoter (Zp) and Rta Promoter (Rp) Transcriptional Activities by Emodin
2.5. Identification of Emodin Responsive Element in Zp
2.6. Emodin Attenuates the Reactivation-Induced Tumorigenic Properties of NPC Cells
2.7. Inhibition of EBV Reactivation by Emodin Decreases Tumor Growth In Vivo
3. Discussion
4. Materials and Methods
4.1. Reagents and Antibodies
4.2. Cell Lines
4.3. EBV Induction and Emodin Treatment
4.4. Evaluation of the Cytotoxicity of Emodin
4.5. Western Blotting Analysis
4.6. Immunofluorecence and Flow Cytometry Analysis
4.7. Determination of the Copy Number of the EBV Genome
4.8. Transfection and Analysis of Luciferase Reporter Activity
4.9. Determination of MN Formation
4.10. Cell Migration Assay
4.11. Cell Invasive Assay
4.12. In Vivo Tumorigenesis Model
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Wu, C.-C.; Chen, M.-S.; Cheng, Y.-J.; Ko, Y.-C.; Lin, S.-F.; Chiu, I.-M.; Chen, J.-Y. Emodin Inhibits EBV Reactivation and Represses NPC Tumorigenesis. Cancers 2019, 11, 1795. https://doi.org/10.3390/cancers11111795
Wu C-C, Chen M-S, Cheng Y-J, Ko Y-C, Lin S-F, Chiu I-M, Chen J-Y. Emodin Inhibits EBV Reactivation and Represses NPC Tumorigenesis. Cancers. 2019; 11(11):1795. https://doi.org/10.3390/cancers11111795
Chicago/Turabian StyleWu, Chung-Chun, Mei-Shu Chen, Yu-Jhen Cheng, Ying-Chieh Ko, Su-Fang Lin, Ing-Ming Chiu, and Jen-Yang Chen. 2019. "Emodin Inhibits EBV Reactivation and Represses NPC Tumorigenesis" Cancers 11, no. 11: 1795. https://doi.org/10.3390/cancers11111795