Therapeutic Zfra4-10 or WWOX7-21 Peptide Induces Complex Formation of WWOX with Selective Protein Targets in Organs that Leads to Cancer Suppression and Spleen Cytotoxic Memory Z Cell Activation In Vivo
Abstract
:1. Introduction
2. Results
2.1. Zfra and WWOX Peptides Suppress Cancer Growth and Metastasis In Vivo
2.2. Ser6 and Ser7 Are Not Involved in Zfra-Mediated Cell Death
2.3. Binding of Zfra with the First WW Domain of WWOX Leads to Nullification of Each Other’s Function in Cancer Suppression
2.4. Increased Binding of Endogenous WWOX with Specific Proteins in Organs of Mice Correlates with Cancer Growth Suppression
2.5. Zfra-Mediated Cancer Suppression Involves Hyal-2 and WWOX of the Hyal-2/pY33-WWOX/SMAD4 Signaling
2.6. Transfer of Purified Activated Z Cells to Recipient Mice Confers Resistance to Tumor Growth
2.7. Zfra Causes WWOX de-Phosphorylation at Y33 and Y61 to Drive Z Cell Activation in the Spleen
2.8. Zfra-Activated Z Cells Relocate to Cancer Lesions to Block Cancer Growth
2.9. Zfra Suppresses pS14-WWOX Expression in the Lung and Thereby Prevents Glioblastoma Cell Metastasis to the Lung
2.10. Sonicated Hyaluronan (HAson) Suppresses Cancer Growth In Vivo via Hyal-2/WWOX Signaling
2.11. Activated Spleen Z Cells Aggressively Attack and Cause Breast Cancer Cell Death In Vitro
3. Discussion
4. Materials and Methods
4.1. cDNA Constructs, Site-Directed Mutagenesis, and Transient Gene Expression
4.2. Antibodies, Immunohistochemistry, and Immunofluorescence Microscopy
4.3. Synthetic Peptides
4.4. Hyaluronan Preparations and Agarose Gel Electrophoresis for Hyaluronan
4.5. Cell Lines
4.6. Z Cell Activation and Purification for Killing Cancer Cells In Vitro by Time-Lapse Microscopy
4.7. Experimental Models: Animal Models and Cancer Cell Growth In Vivo
4.8. Organ Lysates and Co-Immunoprecipitation
4.9. Quantification and Statistical Analysis
4.10. Ethics Approval in Animal Use
5. Conclusions
6. Patents
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Su, W.-P.; Wang, W.-J.; Chang, J.-Y.; Ho, P.-C.; Liu, T.-Y.; Wen, K.-Y.; Kuo, H.-L.; Chen, Y.-J.; Huang, S.-S.; Subhan, D.; et al. Therapeutic Zfra4-10 or WWOX7-21 Peptide Induces Complex Formation of WWOX with Selective Protein Targets in Organs that Leads to Cancer Suppression and Spleen Cytotoxic Memory Z Cell Activation In Vivo. Cancers 2020, 12, 2189. https://doi.org/10.3390/cancers12082189
Su W-P, Wang W-J, Chang J-Y, Ho P-C, Liu T-Y, Wen K-Y, Kuo H-L, Chen Y-J, Huang S-S, Subhan D, et al. Therapeutic Zfra4-10 or WWOX7-21 Peptide Induces Complex Formation of WWOX with Selective Protein Targets in Organs that Leads to Cancer Suppression and Spleen Cytotoxic Memory Z Cell Activation In Vivo. Cancers. 2020; 12(8):2189. https://doi.org/10.3390/cancers12082189
Chicago/Turabian StyleSu, Wan-Pei, Wan-Jen Wang, Jean-Yun Chang, Pei-Chuan Ho, Tsung-Yun Liu, Kuang-Yu Wen, Hsiang-Ling Kuo, Yu-Jie Chen, Shenq-Shyang Huang, Dudekula Subhan, and et al. 2020. "Therapeutic Zfra4-10 or WWOX7-21 Peptide Induces Complex Formation of WWOX with Selective Protein Targets in Organs that Leads to Cancer Suppression and Spleen Cytotoxic Memory Z Cell Activation In Vivo" Cancers 12, no. 8: 2189. https://doi.org/10.3390/cancers12082189