Inhibition of Ceramide Glycosylation Enhances Cisplatin Sensitivity in Cholangiocarcinoma by Limiting the Activation of the ERK Signaling Pathway
<p>Expression of ceramide-metabolizing enzymes in paired CCA tissues. (<b>A</b>) Diagram of the sphingolipids biosynthesis pathways. Expression data were obtained from the GEO database (GSE76297 dataset) for a comparison of: (<b>B</b>) <span class="html-italic">GCS</span> mRNA expression, (<b>C</b>) <span class="html-italic">GBA1</span> mRNA expression, (<b>D</b><span class="html-italic">)</span> <span class="html-italic">GBA2</span> mRNA expression and (<b>E</b>) <span class="html-italic">GBA3</span> mRNA expression. The Mann-Whitney was used to compare the expression between tumor (n = 92) and non-tumor tissues (n = 91) as well as paired tissues. ***, <span class="html-italic">p</span> < 0.001 versus non-tumor tissues.</p> "> Figure 2
<p><span class="html-italic">GCS</span> expression in 29 paired frozen CCA tissues. (<b>A</b>) <span class="html-italic">GCS</span> mRNA expression was determined by qPCR. (<b>B</b>) Cut-off at 1.5-fold change (tumor/adjacent normal) was used for dichotomized <span class="html-italic">GCS</span> mRNA expression in 2 groups. Cut-off value ≤ 1.5-fold change and > 1.5-fold change denoted as low and high <span class="html-italic">GCS</span> expression, respectively. (<b>C</b>) Kaplan-Meier analysis of overall survival in low and high <span class="html-italic">GCS</span> cases. Log Rank test was used for survival analysis. *, <span class="html-italic">p</span> < 0.05 versus adjacent normal tissues.</p> "> Figure 3
<p>Changes of ceramide-metabolizing enzymes upon cisplatin treatment. (<b>A</b>) Respective basal mRNA expression of GCS, GBA1, and GBA2 were determined in two CCA cell lines (KKU-100 and KKU-213A). (<b>B</b>) KKU-100 and KKU-213A were treated with cisplatin at 0, 10, 20, 40, and 60 µM for 24 and 48 h. (<b>C</b>) Respective mRNA expression of GCS, GBA2, and GCS/GBA2 ratio was determined in KKU-100 and KKU-213A after 24 h of cisplatin treatment. Values are expressed as the mean ± SEM of three independent experiments. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01 versus cisplatin at 0 µM. ND: not detected.</p> "> Figure 4
<p>Suppression of GCS reduces CCA cell growth. (<b>A</b>) mRNA and protein levels of GCS after suppression by siRNAs for 24 and 48 h. (<b>B</b>) Cell proliferation after GCS suppression by siRNAs for 0–48 h, (<b>C</b>) PPMP (GCS inhibitor), and (<b>D</b>) co-treatment by siRNAs and PPMP. (<b>E</b>,<b>F</b>) The relative mRNA expression of growth-related genes in siGCS-treated KKU-213A or PPMP-treated KKU-213A were determined using qPCR. Values are expressed as the mean ± SEM of 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 versus siCTRL. The original unedited blot was presented in <a href="#app1-life-12-00351" class="html-app">Figure S1</a>.</p> "> Figure 5
<p>Suppression of GCS enhances cisplatin sensitivity. (<b>A</b>) Inducible mRNA expression of GCS following low-dose cisplatin (0, 10, 20, and 40 μM). Cell viability of KKU-213A was determined after (<b>B</b>) GCS inhibition by siRNAs for 24 h and treated with cisplatin for 48 h, (<b>C</b>) GCS inhibition by PPMP for 24 h and in combination with cisplatin for 48 h, and (<b>D</b>) co-treatment of GCS with siRNAs and PPMP for 24 h plus cisplatin for 48 h. Values are expressed as the mean ± SEM of 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 versus cisplatin at 0 µM.</p> "> Figure 6
<p>Suppression of GCS induces CCA cell apoptosis via the attenuation of ERK activation. KKU-213A was exposed by PPMP alone (10 µM), cisplatin alone (10 or 20 µM), or the combination of both for 24 h. Protein expression potentially involved (<b>A</b>) apoptosis and (<b>B</b>) survival signaling pathway observed by Western blot assay. Relative protein expression was measured by Image J software (version 1.53a). Values are expressed as the mean ± SEM of 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 versus cisplatin at 0 µM. <sup>#</sup> <span class="html-italic">p</span> < 0.05; <sup>##</sup> <span class="html-italic">p</span> < 0.01; <sup>###</sup> <span class="html-italic">p</span> < 0.001 versus cisplatin at 10 or 20 µM. The original unedited blot was presented in <a href="#app1-life-12-00351" class="html-app">Figure S2</a>.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. GEO Database
2.2. CCA Tissue Samples and Cell Lines
2.3. Quantitative Real-Time PCR (qPCR)
2.4. Protein Collection and Immunoblotting
2.5. Inhibition of GCS by Specific-siRNA
2.6. Sulforhodamine B (SRB) Assay
2.7. Cell Proliferation
2.8. Drug Treatment
2.9. Statistical Analysis
3. Results
3.1. Glucosylceramide Synthase (GCS) Expression in Cholangiocarcinoma Tissues
3.2. Altered Expression of Ceramide-Metabolizing Enzymes Following Cisplatin Treatment
3.3. Suppression of GCS Reduces CCA Cell Growth
3.4. Suppression of GCS Enhances Cisplatin Sensitivity
3.5. Suppression of GCS Promotes Cisplatin-Induced CCA Apoptosis through the Inhibition of the ERK Signaling Pathway
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Clinicopathological Feature | Cases (n = 29) | GCS mRNA Expression Levels # | p-Value * | |
---|---|---|---|---|
Low | High | |||
Sex | ||||
Male | 15 | 10 | 5 | 0.474 |
Female | 14 | 11 | 3 | |
Age (years old) | ||||
≤50 | 5 | 4 | 1 | 0.677 |
>50 | 24 | 17 | 7 | |
Tumor stage | ||||
I | 1 | 1 | 0 | 0.690 |
II | 4 | 3 | 1 | |
III | 20 | 15 | 5 | |
IV | 4 | 2 | 2 | |
Normal stage (Lymph node) | ||||
0 | 17 | 13 | 4 | 0.561 |
I | 12 | 8 | 4 | |
Histological | ||||
Papillary carcinoma | 10 | 9 | 1 | 0.124 |
Tubular adenocarcinoma | 19 | 13 | 6 |
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Chueakwon, P.; Jatooratthawichot, P.; Talabnin, K.; Ketudat Cairns, J.R.; Talabnin, C. Inhibition of Ceramide Glycosylation Enhances Cisplatin Sensitivity in Cholangiocarcinoma by Limiting the Activation of the ERK Signaling Pathway. Life 2022, 12, 351. https://doi.org/10.3390/life12030351
Chueakwon P, Jatooratthawichot P, Talabnin K, Ketudat Cairns JR, Talabnin C. Inhibition of Ceramide Glycosylation Enhances Cisplatin Sensitivity in Cholangiocarcinoma by Limiting the Activation of the ERK Signaling Pathway. Life. 2022; 12(3):351. https://doi.org/10.3390/life12030351
Chicago/Turabian StyleChueakwon, Piyasiri, Peeranat Jatooratthawichot, Krajang Talabnin, James R. Ketudat Cairns, and Chutima Talabnin. 2022. "Inhibition of Ceramide Glycosylation Enhances Cisplatin Sensitivity in Cholangiocarcinoma by Limiting the Activation of the ERK Signaling Pathway" Life 12, no. 3: 351. https://doi.org/10.3390/life12030351