Renieramycin T Induces Lung Cancer Cell Apoptosis by Targeting Mcl-1 Degradation: A New Insight in the Mechanism of Action
<p>The structures of renieramycin T (RT) and ecteinascidin 743 (Et 743).</p> "> Figure 2
<p>Renieramycin T (RT) reduced cell viability and induced apoptosis in NSCLC and human normal lung epithelial (BEAS-2B) cell lines. (<b>A</b>) NSCLC and BEAS-2B cell lines were treated with various concentrations of RT (0–25 µM) for 24 h. Percentages of cell viability were determined using the MTT assay. (<b>B</b>) The half maximal inhibitory concentrations (IC<sub>50</sub>) in NSCLC and BEAS-2B cell lines were calculated by comparison with the untreated control. (<b>C</b>–<b>G</b>) H460 and BEAS-2B cell lines were treated with RT (0–25 µM) for 24 h. Hoechst 33342 and propidium iodide (PI) were added. Then, Images were detected by using an inverted fluorescence microscope (a–c). A condensed blue fluorescence of Hoechst 33342 reflected fragmented chromatin in apoptotic cells (c) while a red fluorescence of PI reflected late apoptotic or necrotic cells (b) comparing with no staining condition (a). Percentages of nuclear fragmented and PI positive cells were calculated. (<b>H</b>) H460 was treated with RT (0–25 µM) for 24 h. Apoptotic and necrotic cells were determined using annexin V-FITC/PI staining with flow cytometry. (<b>I</b>) Percentages of cells at each stage were calculated. Data represented the mean ± SEM (n = 3) (* 0.01 ≤ <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, compared with the untreated control).</p> "> Figure 3
<p>Renieramycin T (RT) induced activation of PARP, caspase-3, and caspase-9 in the H460 cell line. Moreover, RT also significantly up-regulated p53 and down-regulated Mcl-1 in the H460 cell line. H460 cells were treated with RT (0–25 µM) for 24 h. (<b>A</b>) and (<b>C</b>) Apoptotis-related proteins were measured with Western blot analysis. The blots were reprobed with β-actin to confirm equal loading of each of the protein samples. (<b>B</b>) and (<b>D</b>) The relative protein levels were calculated by densitometry. Data represented the mean ± SEM (n = 3) (* 0.01 ≤ <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, compared with the untreated control).</p> "> Figure 4
<p>Renieramycin T (RT) induced ubiquitin-mediated Mcl-1 proteasomal degradation. (<b>A</b>) Cycloheximide (CHX) chasing assay was performed to measure Mcl-1 half-lives. H460 cells were treated with RT (0–5 µM) with or without 50 µg/mL CHX as indicated by the time in h. Western blot analysis was performed for determined Mcl-1 levels. The blots were reprobed with β-actin to confirm equal loading of each of the protein samples. (<b>B</b>) The relative protein levels were calculated by densitometry (** <span class="html-italic">p</span> < 0.01, compared with the untreated control at 0 h, # 0.01 ≤ <span class="html-italic">p</span> < 0.05, ## <span class="html-italic">p</span> < 0.01, compared with the untreated control at the same time). (<b>C</b>) Mcl-1 half-lives were calculated. (<b>D</b>) H460 cell line was treated with RT (0–5 µM) with or without MG132 (0–20 µM) for 4 h. Mcl-1 expression levels were measured using Western blot analysis. The blots were reprobed with β-actin to confirm equal loading of each of the protein samples. (<b>E</b>) The reversal of RT-mediated down-regulation of Mcl-1 levels by MG132 was calculated by densitometry compared to the non-MG132 treated group (* 0.01 ≤ <span class="html-italic">p</span> < 0.05, compared with the non-MG132 treated group). (<b>F</b>) H460 was treated with RT (5 µM) and MG132 (10 µM) for 4 h. Then, protein lysates were collected subsequent to Mcl-1 immunoprecipitation, and the ubiquitinated protein levels were measured by Western blotting. (<b>G</b>) Ub-Mcl-1 levels were quantified using densitometry (* <span class="html-italic">p</span> < 0.01, compared with the untreated control) All data represented the mean ± SEM (n = 3).</p> "> Figure 5
<p>Renieramycin T (RT) enhances apoptosis induction through Mcl-1 proteasomal degradation. Normally, Mcl-1 forms complex with Bak to inhibit its apoptotic function, but when Mcl-1 is degraded through the ubiquitin-mediated proteasomal degradation by treatment of RT, Bak is relieved. Activated Bak forms oligomerization that can permeabilize the outer membrane of mitochondria and release cytochrome c to initiate the apoptosis mechanism.</p> ">
Abstract
:1. Introduction
2. Results
2.1. The Cytotoxicity and Apoptosis-Inducing Effect of Renieramycin T
2.2. Renieramycin T Promotes Apoptosis by Targeting Mcl-1 to Proteasomal Degradation
2.3. Renieramycin T Decreases Mcl-1 Through the Induction of Mcl-1 Proteasomal Degradation
3. Discussion
4. Materials and Methods
4.1. Reagents and Antibodies
4.2. Isolation of Renieramycin T (RT)
4.3. Preparation of the RT Stock Solution
4.4. Cell Lines and Culture
4.5. Cell Viability Aassay
4.6. Nuclear Staining Assay
4.7. Annexin V-FITC/PI Staining Apoptotic Assay
4.8. Western Blot Analysis
4.9. Cycloheximide (CHX) Chasing Assay
4.10. Immunoprecipitation Assay
4.11. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Petsri, K.; Chamni, S.; Suwanborirux, K.; Saito, N.; Chanvorachote, P. Renieramycin T Induces Lung Cancer Cell Apoptosis by Targeting Mcl-1 Degradation: A New Insight in the Mechanism of Action. Mar. Drugs 2019, 17, 301. https://doi.org/10.3390/md17050301
Petsri K, Chamni S, Suwanborirux K, Saito N, Chanvorachote P. Renieramycin T Induces Lung Cancer Cell Apoptosis by Targeting Mcl-1 Degradation: A New Insight in the Mechanism of Action. Marine Drugs. 2019; 17(5):301. https://doi.org/10.3390/md17050301
Chicago/Turabian StylePetsri, Korrakod, Supakarn Chamni, Khanit Suwanborirux, Naoki Saito, and Pithi Chanvorachote. 2019. "Renieramycin T Induces Lung Cancer Cell Apoptosis by Targeting Mcl-1 Degradation: A New Insight in the Mechanism of Action" Marine Drugs 17, no. 5: 301. https://doi.org/10.3390/md17050301