WWOX Possesses N-Terminal Cell Surface-Exposed Epitopes WWOX7-21 and WWOX7-11 for Signaling Cancer Growth Suppression and Prevention In Vivo
<p>WWOX7-21 and WWOX7-11 peptides suppressed cancer growth in vivo. (<b>A</b>) A schematic primary structure of the first WW domain of WWOX is shown. (<b>B</b>,<b>C</b>) BALB/c mice were inoculated with B16F10 melanoma cells in the left and right flanks (red and blue lines of growth curves). A week after, mice received indicated peptides (1 mM in 100 µL PBS) via tail vein injections. WWOX7-21, WWOX7-11 and WWOX286-299 blocked B16F10 growth. pS14-WWOX7-21 was ineffective. (<b>D</b>) The end-point tumor volumes are shown (<span class="html-italic">n</span> = 6; mean ± SD).</p> "> Figure 2
<p>WWOX7-11 peptide is most potent in suppressing cancer growth in vivo (<b>A</b>) Each NOD-SCID mouse received an indicated peptide via subcutaneous injection in one side of the flanks, and B16F10 cells inoculated simultaneously in the other side. WWOX7-11 blocked B16F10 growth (<span class="html-italic">n</span> = 3; mean ± SD). (<b>B</b>,<b>C</b>) Scrambled peptides of WWOX7-11 (AGLDD) did not block melanoma growth in nude mice (<span class="html-italic">n</span> = 4; mean ± SD). The tumor growth curves and the end-point tumor sizes are shown. (<b>D</b>) BALB/c mice received tail vein injections of WWOX7-21 once per week for 3 consecutive weeks, followed by inoculating cancer cells in both flanks. The growth of B16F10 cancer cells was blocked (representative data from 2 experiments). (<b>E</b>) Zfra4-10 and WWOX7-11 peptides were resuspended in sterile Milli-Q water (400 µM), and allowed to sit for 3 h in the room temperature. Partial self-polymerization of the peptides is shown. (<b>F</b>) Under similar conditions, Zfra4-10 and Zfra1-15(S8G) were resuspended in PBS and incubated at room temperature for 3 h. Zfra4-10 underwent polymerization, and the S8G mutant failed to polymerize.</p> "> Figure 3
<p>WWOX7-21 peptide suppresses melanoma metastasis, whereas pS14-WWOX7-21 peptide induces cytotoxic T cell expansion and fails to block cancer metastasis in vivo. (<b>A</b>) BALB/c mice received subcutaneous injections of WWOX7-21 peptide and became resistant to the metastasis of melanoma B16F10 cells to the lung and liver. Other peptides were ineffective. (<b>B,C</b>) pS14-WWOX7-21 peptide significantly induced the expansion of CD4<sup>+</sup> and CD8α<sup>+</sup> T and CD19<sup>+</sup> B cells in the germinal centers, but had no effect on Foxp3<sup>+</sup> Treg cells in BALB/c mice. Scale bar = 50 µm.</p> "> Figure 4
<p>WWOX7-21 and WWOX286-299 peptides colocalize with cell membrane type II TGFβ receptor (TβRII). (<b>A</b>) WWOX-negative MDA-MB-231 cells were incubated with WWOX7-21 or WWOX286-299 peptide at 4 °C for 30 min, followed by processing immunostaining using our generated peptide antibodies. These peptides were shown to colocalize with membrane TβRII. Cells were not permeabilized with Triton X-100. In the negative controls, no primary antibodies were used. (<b>B</b>) In control experiments, cells were stained for ERK1/2 to show its nuclear localization in Triton X-100-permeabilized cells. No signal was shown in non-permeabilized cells. (<b>C</b>) Colocalization of TβRII with WWOX7-21 and WWOX286-299 is shown in MDA-MB-231 cells, as determined by confocal microscopy. (Magnification 400×). (<b>D</b>) <span class="html-italic">Wwox</span><sup>+/+</sup> wild type MEF cells were pretreated with WWOX286-299 peptide for 5 min at 37 °C, followed by treating with TGF-β1 (10 ng/mL) for indicated times. The WWOX286-299 peptide colocalized with TβRII, and TGF-β1 appeared to induce internalization of the peptide/TβRII complex.</p> "> Figure 5
<p>pS14-WWOX7-21 peptide blocked ceritinib-mediated 4T1 stem cell sphere explosion and death. (<b>A</b>,<b>B</b>) 4T1 stem cell spheres were treated with an indicated antiserum (1/100 dilution) for 30 min, and then exposed to ceritinib (30 µM) for time-lapse fluorescent microscopy at 37 °C. DAPI uptake in the nuclei (blue) by live cells indicates an increased nuclear membrane permeability, and PI uptake by nuclei (red) indicates cell death (mean ± SD; <span class="html-italic">n</span> = 3; SD in black shaded areas). The red stars show the initiation of stem cell sphere explosion and death. Representative changes in sphere morphology with time are shown. (<b>C</b>,<b>D</b>) pS14-WWOX7-21 peptide strongly blocked ceritinib-mediated cell death and sphere explosion; however, WWOX7-21 peptide drastically enhanced the cell death and sphere explosion event. (<b>E</b>) The time of initiation of 4T1 cell sphere explosion is shown (<span class="html-italic">n</span> = 3). (<b>F</b>) Summary of enhancers and inhibitors for ceritinib-mediated cell death.</p> "> Figure 6
<p>Ceritinib induces 4T1 cell apoptosis by inducing calcium influx and upregulating pY33-WWOX. (<b>A</b>–<b>C</b>) 4T1 cells were treated with an indicated concentration of ceritinib for 24 h at 37 ℃ and were subjected to MTT assay for cell viability (<span class="html-italic">n</span> = 3, * <span class="html-italic">p</span> < 0.05; **** <span class="html-italic">p</span> < 0.0001) (<b>A</b>), and apoptosis by DNA fragmentation analysis, where staurosporine (St) treatment is regarded as a positive control (<b>B</b>), and cell cycle analysis (<b>C</b>). Note that ceritinib induced apoptosis by increasing the percentages of SubG1 phase (<span class="html-italic">n</span> = 3, ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001). (<b>D</b>–<b>F</b>) When 4T1 cells were treated with ceritinib for indicated times at 37 °C, decreased S14 phosphorylation but increased Y33 phosphorylation in WWOX was observed. Quantification of protein expression was normalized to β-actin, and then normalized to the control. (<span class="html-italic">n</span> = 3, * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01). (<b>G</b>,<b>H</b>) Ceritinib rapidly induced Ca<sup>2+</sup> influx (green fluorescent Fluo-8) and simultaneous DAPI uptake (blue fluorescence) in 4T1 cells in 20 min prior to cell death (PI uptake; red fluorescence). Exposure of 4T1 cells to EGTA for 10 min prior to treating with ceritinib resulted in retarded cell death and abolished Ca<sup>2+</sup> influx, whereas DAPI uptake was enhanced.</p> "> Figure 7
<p>WWOX peptides counteract the ceritinib-mediated apoptosis via regulating ERK phosphorylation and IkBα/WWOX/ERK signaling. (<b>A</b>,<b>B</b>) Ceritinib rapidly suppressed the phosphorylation of ERK1/2 in 4T1 cells. A time-related nuclear accumulation of ERK2 is shown. Similar results were observed for ERK1/2 using specific antibodies. (<b>C</b>) Compared to WWOX7-21 peptide, pS14-WWOX7-21 peptide sustained phosphorylation of ERK and JNK in 4T1 cells. (<b>D</b>) 4T1 cells were treated with an indicated peptide (30 μM) for 30 min, and then exposed to ceritinib (30 μM) for 60 min, prior to processing cytosolic and nuclear fractionation and Western blotting. (<b>E</b>) 4T1 cells were cotreated with ceritinib (30 μM) and an indicated chemical for time-lapse microscopy. p53 inhibitor pifithin-μ and -α (50 μM) retarded the ceritinib-mediated sphere explosion and apoptosis. p53 activator quinacrine (50 µM) accelerated ceritinib-mediated apoptosis. (<b>F</b>) Phosphatase inhibitors (10 μL) enhanced ceritinib-mediated sphere explosion and apoptosis, whereas protease inhibitor leuhistin (30 μM) marginally retarded the effect of ceritinib (<span class="html-italic">n</span> = 3, ** <span class="html-italic">p</span> < 0.05; * <span class="html-italic">p</span> < 0.1). (<b>G</b>,<b>H</b>) COS7 cells were transiently transfected with ECFP-IkBα, EGFP-ERK and DsRed-WWOX cDNA expression constructs. By thee protein/protein time-lapse FRET microscopy, ceritinib induced the signaling from IkBα to ERK and then to WWOX via energy transfer. In controls, no signaling is observed for ECFP, EGFP and DsRed. (<b>I</b>) A schematic graph for ceritinib signaling is shown, namely upregulation of pY33-WWOX, downregulation of p-ERK, dissociation of the IkBα/WWOX/ERK complex, and nuclear translocation of pY33-WWOX to cause apoptosis. Additionally, ceritinib induces cancer stem cell sphere explosion and death. Ceritinib-mediated apoptosis of single cells is switched to bubbling cell death at room temperature.</p> ">
Abstract
:1. Introduction
2. Results
2.1. WWOX7-21 and WWOX7-11 Peptides Effectively Inhibit Melanoma Cell Growth in Both Immune Competent and Deficient Mice
2.2. WWOX7-21 Peptide Effectively Prevents Skin Cancer and Melanoma Cell Growth In Vivo
2.3. WWOX7-21 Peptide Blocks Melanoma Cell Metastasis
2.4. pS14-WWOX7-21 Peptide Dramatically Induces Cytotoxic T Cell Expansion but Fails to Block Cancer Cell Metastasis
2.5. WWOX7-21 and WWOX286-299 Peptides Bind Cell Surface and Colocalize with Membrane Type II TGF-β Receptor (TβRII)
2.6. WWOX Is Clustered in the Cell Membrane
2.7. Ceritinib Mediates 4T1 Cell Sphere Shinkage (Pre-Explosion Stage) and then Explosion and Death (Explosion Stage)
2.8. Treatment of 4T1 Cells with pS14-WWOX Antibody Accelerates Ceritinib-Mediated Sphere Explosion and Cell Death
2.9. pS14-WWOX Peptide Protects 4T1 Cells from Ceritinib-Mediated Death In Vitro
2.10. Ceritinib Upregulates Proapoptotic pY33-WWOX and Meanwhile Induces Ca2+ Influx for Leading to Apoptosis of 4T1 Cells
2.11. WWOX Peptides Counteract the Ceritinib-Mediated Apoptosis via Regulating ERK Phosphorylation
2.12. Endogenous p53 and Aminopeptidase M Enhance Ceritinib-Mediated Cell Sphere Explosion and Cell Death
2.13. Ceritinib Suppresses the Prosurvival IkBα/ERK/WWOX Signaling to Cause Cell Death
3. Discussion
3.1. pY33 Switching to pS14 for Cancer Promotion in WWOX
3.2. Role of TβRII in Anchoring WWOX Peptides
3.3. WWOX7-21 and pS14-WWOX7-21 Peptides Recapitulate the Functional Properties of Endogenous WWOX
3.4. Zfra Induces the Hyal-2/WWOX/Smad4 Signaling for Cancer Suppression
3.5. WWOX Peptides and Their Anticancer Activities in Immune Competent and Deficient Mice
3.6. pS14-WWOX7-21 Peptide Induces the Expansion of Spleen CD8α+ T and CD19+ B Cells
3.7. pS14-WWOX7-21 Peptide Probably Drives the IkBα/WWOX/ERK Signaling for T/B Cell Maturation
3.8. The Complex of pY33-WWOX and Hyal-2 Causes Apoptosis in the Nucleus
3.9. Ceritinib Upregulates pY33-WWOX, Downregulates p-ERK, Induces Ca+2 Influx, and Ultimately Generates DNA Fragmentation
4. Materials and Methods
4.1. Cell Lines
4.2. Structure Simulation and Peptide Synthesis
4.3. Cancer Growth and Immune Cell Differentiation in Mice
4.4. Antibodies, Immunohistochemistry, and Immunofluorescence Microscopy
4.5. Time-Lapse Microscopy for 4T1 Stem Cell Sphere Explosion and Death
4.6. Time-Lapse tri-Molecular Förster Resonance Energy Transfer (FRET) Microscopy
4.7. Data Presentation and Statistical Analysis
4.8. Ethics Approval in Animal Use
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Wang, W.-J.; Ho, P.-C.; Nagarajan, G.; Chen, Y.-A.; Kuo, H.-L.; Subhan, D.; Su, W.-P.; Chang, J.-Y.; Lu, C.-Y.; Chang, K.T.; et al. WWOX Possesses N-Terminal Cell Surface-Exposed Epitopes WWOX7-21 and WWOX7-11 for Signaling Cancer Growth Suppression and Prevention In Vivo. Cancers 2019, 11, 1818. https://doi.org/10.3390/cancers11111818
Wang W-J, Ho P-C, Nagarajan G, Chen Y-A, Kuo H-L, Subhan D, Su W-P, Chang J-Y, Lu C-Y, Chang KT, et al. WWOX Possesses N-Terminal Cell Surface-Exposed Epitopes WWOX7-21 and WWOX7-11 for Signaling Cancer Growth Suppression and Prevention In Vivo. Cancers. 2019; 11(11):1818. https://doi.org/10.3390/cancers11111818
Chicago/Turabian StyleWang, Wan-Jen, Pei-Chuan Ho, Ganesan Nagarajan, Yu-An Chen, Hsiang-Ling Kuo, Dudekula Subhan, Wan-Pei Su, Jean-Yun Chang, Chen-Yu Lu, Katarina T. Chang, and et al. 2019. "WWOX Possesses N-Terminal Cell Surface-Exposed Epitopes WWOX7-21 and WWOX7-11 for Signaling Cancer Growth Suppression and Prevention In Vivo" Cancers 11, no. 11: 1818. https://doi.org/10.3390/cancers11111818