Laminarin-Derived from Brown Algae Suppresses the Growth of Ovarian Cancer Cells via Mitochondrial Dysfunction and ER Stress
<p>Cell viability and cell cycle progression in laminarin-treated ES2 and OV90 cells. (<b>A</b>) Structure of laminarin derived from <span class="html-italic">Laminaria digitate</span>. (<b>B</b>,<b>C</b>) Cell proliferation analysis performed using BrdU reveals that laminarin (0.1, 0.25, 0.5, 1 and 2 mg/mL) decreased cell proliferation in a dose-dependent manner in ES2 (<b>B</b>) and OV90 (<b>C</b>) cells. Results are calculated compared with vehicle-treated control (viability considered as 100%). (<b>D</b>,<b>E</b>) Alterations in cell cycle progression were analyzed by flow cytometry using propidium iodide (PI) staining in laminarin-treated ES2 (<b>D</b>) and OV90 (<b>E</b>) cells. The percentages in each cell cycle stage are shown. *** <span class="html-italic">p</span> < 0.001, ** <span class="html-italic">p</span> < 0.01, * <span class="html-italic">p</span> < 0.05 compared with vehicle-treated control cells.</p> "> Figure 2
<p>Laminarin inhibited intracellular signal transduction in ovarian cancer (OC) cells. (<b>A</b>–<b>G</b>) Immunoblotting showing the phosphorylation of cyclin D1 (<b>A</b>), AKT (<b>B</b>), P70S6K (<b>C</b>), S6 (<b>D</b>), extracellular signal-regulated kinase 1/2 (ERK1/2) (<b>E</b>), c-Jun N-terminal kinase (JNK) (<b>F</b>), and P38 (<b>G</b>) proteins in laminarin (0.5, 1, and 2 mg/mL)-treated OC cells. Phosphoprotein intensities were normalized to the total protein levels compared with vehicle-treated controls. *** <span class="html-italic">p</span> < 0.001, ** <span class="html-italic">p</span> < 0.01, and * <span class="html-italic">p</span> < 0.05 indicate statistical significance compared with non-treated cells.</p> "> Figure 3
<p>Inhibition of PI3K and MAPK signals in laminarin-treated OC cells. OC cells were treated with inhibitors, including LY294002 (20 μΜ, AKT), U0126 (10 µM, ERK1/2), SB203580 (20 µM, p38), SP600125 (20 µM, JNK), and laminarin (2 mg/mL) for western blot analysis to determine levels of AKT (<b>A</b>), P70S6K (<b>B</b>), S6 (<b>C</b>), ERK1/2 (<b>D</b>), JNK (<b>E</b>), and P38 (<b>F</b>). Phosphoprotein intensities were normalized to the total protein levels compared with vehicle-treated controls. *** <span class="html-italic">p</span> < 0.001, ** <span class="html-italic">p</span> < 0.01, and * <span class="html-italic">p</span> < 0.05 indicate statistical significance compared with non-treated cells.</p> "> Figure 4
<p>Laminarin induced apoptosis of human OC cells. (<b>A</b>,<b>B</b>) DNA fragmentation was observed using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining (red). The nuclei of cells were counterstained using 4′,6-diamidino-2-phenylindole (DAPI) (blue). The scale bar represents 20 μm (in the first horizontal panel set) and 5 μm (in the second horizontal panel set). The apoptotic ES2 (<b>C</b>) and OV90 (<b>D</b>) cells treated with laminarin were measured using annexin V and propidium iodide (PI) fluorescent dyes. Reactive oxygen species (ROS) production in laminarin-treated ES2 (<b>E</b>) and OV90 (<b>F</b>) cells was observed using dichlorofluorescein (DCF) fluorescence by flow cytometry compared with vehicle-treated cells. (<b>G</b>,<b>H</b>) Apoptotic signals induced by laminarin were observed using western blot analysis in OC cells. Apoptotic protein intensities were normalized to alpha-tubulin (TUBA) compared with vehicle-treated cells. *** <span class="html-italic">p</span> < 0.001, ** <span class="html-italic">p</span> < 0.01, and * <span class="html-italic">p</span> < 0.05 indicate statistical significance compared with non-treated cells.</p> "> Figure 5
<p>Effects of laminarin on calcium homeostasis and mitochondria membrane potential (MMP) in ES2 and OV90 cells. (<b>A</b>,<b>B</b>) Flow cytometry analysis using fluo-4 showed cytosolic calcium in response to laminarin (0.1, 0.25, 0.5, 1, and 2 mg/mL). Flow cytometry analysis using rhod-2 revealed mitochondrial calcium levels in ES2 (<b>C</b>) and OV90 (<b>D</b>) cells following laminarin treatment for 48 h. Flow cytometry analysis indicated MMP in ES2 (<b>E</b>) and OV90 (<b>F</b>) cells that were treated with various laminarin concentrations. Loss of MMP was analyzed using JC-1 red and green fluorescence ratios. *** <span class="html-italic">p</span> < 0.001, ** <span class="html-italic">p</span> < 0.01, and * <span class="html-italic">p</span> < 0.05 indicate statistical significance compared with non-treated cells.</p> "> Figure 6
<p>Inhibition of calcium influx in laminarin-treated OC cells. The number of late apoptotic ES2 (<b>A</b>) and OV90 (<b>B</b>) cells co-treated with laminarin and calcium chelators (2-aminoethoxydiphenyl borate (2-APB), 1,2-<span class="html-italic">bis</span>(2-aminophenoxy)ethane-<span class="html-italic">N</span>,<span class="html-italic">N</span>,<span class="html-italic">N</span>′,<span class="html-italic">N</span>′-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA), and ruthenium red) was measured using annexin V and PI staining. (<b>C</b>,<b>D</b>) Flow cytometry analysis using fluo-4 showed cytosolic calcium in OC cells co-treated with laminarin and calcium chelators. (<b>E</b>,<b>F</b>) Flow cytometry analysis using rhod-2 revealed mitochondrial calcium levels in ES2 and OV90 cells following treatment with laminarin and calcium chelators. (<b>G</b>,<b>H</b>) Loss of MMP was analyzed using JC-1 red and green fluorescence ratios by treatment of ES2 and OV90 cells with laminarin and a calcium chelator. *** <span class="html-italic">p</span> < 0.001, ** <span class="html-italic">p</span> < 0.01, and * <span class="html-italic">p</span> < 0.05 indicate statistical significance compared with non-treated cells. ‘a’ indicates statistical significance (<span class="html-italic">p</span> < 0.05) compared with laminarin-treated cells.</p> "> Figure 7
<p>Laminarin induced ER stress in OC cells. (<b>A</b>–<b>F</b>) Activation of ER stress-associated proteins, including inositol-requiring enzyme-1α (IRE1α), activating transcription factor 6α (ATF6α), growth arrest and DNA damage 153 (GADD153), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), and 78-kDa glucose-regulated protein (GRP78), was analyzed by western blotting of ES2 and OV90 cells treated with various concentrations of laminarin (0.5, 1 and 2 mg/mL). Target protein intensity was detected and analyzed relative to total protein or TUBA protein. *** <span class="html-italic">p</span> < 0.001, ** <span class="html-italic">p</span> < 0.01, and * <span class="html-italic">p</span> < 0.05 indicate statistical significance compared with non-treated cells.</p> "> Figure 8
<p>Laminarin altered intracellular signaling related to ER-mitochondria contact proteins and autophagy. (<b>A</b>–<b>D</b>) Expression of ER-mitochondrial tethering proteins, including IP3R1, IP3R2, GRP75, and MFN2, was analyzed by western blot analysis of ES2 and OV90 cells treated with various concentrations of laminarin (0.5, 1, and 2 mg/mL). (<b>E</b>,<b>F</b>) Expression of autophagic proteins, including ULK1 and p62, was analyzed by western blot analysis of ES2 and OV90 cells. Target protein intensity was detected and analyzed relative to total protein or TUBA protein. *** <span class="html-italic">p</span> < 0.001, ** <span class="html-italic">p</span> < 0.01, and * <span class="html-italic">p</span> < 0.05 indicate statistical significance compared with non-treated cells.</p> "> Figure 9
<p>Effects of laminarin on cytotoxicity and tumor formation in vivo. (<b>A</b>) Zebrafish embryos, with their egg shells removed, were treated with various concentrations of laminarin (0.5, 1, and 2 mg/mL) for 24 h. Under light microscopy, normal zebrafish viability and development were observed following laminarin treatment. (<b>B</b>,<b>C</b>) Laminarin-treated OC cells were injected into zebrafish yolks to form a xenograft model. Zebrafish were incubated in 24-well plates containing Danieau’s solution with 0.003% phenylthiourea at 28.5 °C for 72 h. CM-Dil dye stained the tumor cells, and they were quantified by ImageJ software. *** <span class="html-italic">p</span> < 0.001, ** <span class="html-italic">p</span> < 0.01, and * <span class="html-italic">p</span> < 0.05 indicate statistical significance compared with non-treated embryos.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Laminarin Reduces Cell Proliferation and Induces SubG1 Phase Arrest in EOC Cells
2.2. Laminarin Inhibits PI3K/MAPK Intracellular Signaling Pathways in Human EOC Cells
2.3. Laminarin Alters Programmed Cell Death in Human EOC Cells
2.4. Effects of Laminarin on Calcium Ion Levels and MMP in EOC Cells
2.5. Laminarin Induces Cell Death and Loss of MMP through Calcium Regulation
2.6. Laminarin Induces ER Stress in Human EOC Cells
2.7. Laminarin Alters ER-Mitochondrial Mediated Proteins and Autophagy Proteins
2.8. Cytotoxicity of Laminarin in a Zebrafish Xenograft Model
3. Discussion
4. Materials and Methods
4.1. Reagents
4.2. Cell Culture
4.3. Cell Proliferation Assay
4.4. TUNEL Assay
4.5. Annexin V and PI Staining
4.6. Cell Cycle Assay
4.7. Cellular ROS Determination
4.8. Measurement of Intracellular Concentrations of Free Calcium
4.9. Measurement of Mitochondrial Calcium Concentration
4.10. JC-1 MMP Assay
4.11. Western Blot Analysis
4.12. Toxicity Assays Using a Zebrafish Model
4.13. Xenografts
4.14. Statistical Analyses
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Bae, H.; Song, G.; Lee, J.-Y.; Hong, T.; Chang, M.-J.; Lim, W. Laminarin-Derived from Brown Algae Suppresses the Growth of Ovarian Cancer Cells via Mitochondrial Dysfunction and ER Stress. Mar. Drugs 2020, 18, 152. https://doi.org/10.3390/md18030152
Bae H, Song G, Lee J-Y, Hong T, Chang M-J, Lim W. Laminarin-Derived from Brown Algae Suppresses the Growth of Ovarian Cancer Cells via Mitochondrial Dysfunction and ER Stress. Marine Drugs. 2020; 18(3):152. https://doi.org/10.3390/md18030152
Chicago/Turabian StyleBae, Hyocheol, Gwonhwa Song, Jin-Young Lee, Taeyeon Hong, Moon-Jeong Chang, and Whasun Lim. 2020. "Laminarin-Derived from Brown Algae Suppresses the Growth of Ovarian Cancer Cells via Mitochondrial Dysfunction and ER Stress" Marine Drugs 18, no. 3: 152. https://doi.org/10.3390/md18030152