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

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 Hyal-2/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.

Molecular Functions of WWOX Potentially Involved in Cancer Development

“…pS14-WWOX is expressed in the B16F10 cells infiltrated into this organ, and the injection of Zfra via tail veins prevents B16F10 cells from metastasizing and inhibits the phosphorylation of WWOX on its serine 14 [ 109 , 110 ]. Additionally, the injection of pS14-WWOX7-21 peptide promotes B16F10 cell growth [ 52 , 53 ]. The pS14-WWOX7-21 peptide blocks, while pS14-WWOX antiserum promotes, ceritinib-mediated 4T1 breast cancer stem cells apoptosis [ 53 ].…”

“…Fourth, Chang et al reported that different peptides of WWOX (WWOX286-299, WWOX7-21, and WWOX7-11) injected into the tail vein of mice inhibit the growth of melanoma B16F12 cells inoculated into the flanks, revealing their potential use in anticancer treatments [ 52 , 53 ]. Additionally, the WWOX7-21 peptide promotes ceritinib-mediated 4T1 breast-cancer stem cells apoptosis [ 53 ].…”

Normal cells repel WWOX-negative or -dysfunctional cancer cells via WWOX cell surface epitope 286-299

“…Alterations in these pathways due to WWOX dysfunction may facilitate disease progression 7 – 13 . Aberrant WWOX phosphorylation also enhances the progression of cancer and Alzheimer’s disease (AD) 9 , 14 – 16 . For example, transition of proapoptotic pY33-WWOX to prosurvival pS14-WWOX promotes the progression of both cancer 15 , 16 and AD 17 .…”

“…Aberrant WWOX phosphorylation also enhances the progression of cancer and Alzheimer’s disease (AD) 9 , 14 – 16 . For example, transition of proapoptotic pY33-WWOX to prosurvival pS14-WWOX promotes the progression of both cancer 15 , 16 and AD 17 . Human newborns deficient in WWOX suffer severe neural diseases, metabolic disorders, and early death, but fail to form tumors spontaneously 14 , 18 – 23 .…”

“…When the signaling complex WWOX/Hyal-2/Smad4 is transiently overexpressed, TGF-β or hyaluronan induces internalization of the signaling complex to relocate the nucleus for causing cell death 7 , 32 . Most recently, we have identified two cell surface-exposed WWOX epitopes, namely WWOX7-21 and WWOX286-299 16 , 33 . Synthetic WWOX7-21 peptide potently enhances ceritinib-mediated breast 4T1 cell death 33 .…”