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

Wan Pei Su, 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, Yu An Chen, Chen Yu Lu, Chia Yun Wu, Sing Ru Lin, Ming Hui Lee, Ming Fu Chiang, Chun I. Sze, Nan Shan Chang

Research output: Contribution to journalArticlepeer-review

Abstract

Synthetic Zfra4-10 and WWOX7-21 peptides strongly suppress cancer growth in vivo. Hypothetically, Zfra4-10 binds to the membrane Hyal-2 of spleen Z cells and activates the Hyal2/WWOX/SMAD4 signaling for cytotoxic Z cell activation to kill cancer cells. Stimulation of membrane WWOX in the signaling complex by a WWOX epitope peptide, WWOX7-21, is likely to activate the signaling. Here, mice receiving Zfra4-10 or WWOX7-21 peptide alone exhibited an increased binding of endogenous tumor suppressor WWOX with ERK, C1qBP, NF-κB, Iba1, p21, CD133, JNK1, COX2, Oct4, and GFAP in the spleen, brain, and/or lung which led to cancer suppression. However, when in combination, Zfra4-10 and WWOX7-21 reduced the binding of WWOX with target proteins and allowed tumor growth in vivo. In addition to Zfra4-10 and WWOX7-21 peptides, stimulating the membrane Hyal-2/WWOX complex with Hyal-2 antibody and sonicated hyaluronan (HAson) induced Z cell activation for killing cancer cells in vivo and in vitro. Mechanistically, Zfra4-10 binds to membrane Hyal-2, induces dephosphorylation of WWOX at pY33 and pY61, and drives Z cell activation for the anticancer response. Thus, Zfra4-10 and WWOX7-21 peptides, HAson, and the Hyal-2 antibody are of therapeutic potential for cancer suppression.

Original languageEnglish
Article number2189
Pages (from-to)1-22
Number of pages22
JournalCancers
Volume12
Issue number8
DOIs
Publication statusPublished - 2020 Aug

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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