Wwox possesses n-terminal cell surface-exposed epitopes wwox7-21 and wwox7-11 for signaling cancer growth suppression and prevention in vivo

Wan Jen Wang, 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, Sing Ru Lin, Ming Hui Lee, Nan Shan Chang

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Abstract

Membrane hyaluronidase Hyal-2 supports cancer cell growth. Inhibition of Hyal-2 by specific antibody against Hyal-2 or pY216-Hyal-2 leads to cancer growth suppression and prevention in vivo. By immunoelectron microscopy, tumor suppressor WWOX is shown to be anchored, in part, in the cell membrane by Hyal-2. Alternatively, WWOX undergoes self-polymerization and localizes in the cell membrane. Proapoptotic pY33-WWOX binds Hyal-2, and TGF-β induces internalization of the pY33-WWOX/Hyal-2 complex to the nucleus for causing cell death. In contrast, when pY33 is downregulated and pS14 upregulated in WWOX, pS14-WWOX supports cancer growth in vivo. Here, we investigated whether membrane WWOX receives extracellular signals via surface-exposed epitopes, especially at the S14 area, that signals for cancer growth suppression and prevention. By using a simulated 3-dimentional structure and generated specific antibodies, WWOX epitopes were determined at amino acid #7 to 21 and #286 to 299. Synthetic WWOX7-21 peptide, or truncation to 5-amino acid WWOX7-11, significantly suppressed and prevented the growth and metastasis of melanoma and skin cancer cells in mice. Time-lapse microscopy revealed that WWOX7-21 peptide potently enhanced the explosion and death of 4T1 breast cancer stem cell spheres by ceritinib. This is due to rapid upregulation of proapoptotic pY33-WWOX, downregulation of prosurvival pERK, prompt increases in Ca2+ influx, and disruption of the IkBα/WWOX/ERK prosurvival signaling. In contrast, pS14-WWOX7-21 peptide dramatically increased cancer growth in vivo and protected cancer cells from ceritinib-mediated apoptosis in vitro, due to a prolonged ERK phosphorylation. Further, specific antibody against pS14-WWOX significantly enhanced the ceritinib-induced apoptosis. Together, the N-terminal epitopes WWOX7-21 and WWOX7-11 are potent in blocking cancer growth in vivo. WWOX7-21 and WWOX7-11 peptides and pS14-WWOX antibody are of therapeutic values in suppressing and preventing cancer growth in vivo.

Original languageEnglish
Article number1818
JournalCancers
Volume11
Issue number11
DOIs
Publication statusPublished - 2019 Nov

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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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., Lin, S. R., Lee, M. H., & Chang, N. S. (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(11), [1818]. https://doi.org/10.3390/cancers11111818