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

Yu-Jie Chen,Shur-Tzu Chen,Nan-Shan Chang,Yu-An Chen,Kuan-Ting Lee,Hsiang-Ling Kuo,Pei-Yi Chou,Tsung-Yun Liu,Pin-Jun Chen,Yong-Da Sie

doi:10.1038/s42003-021-02271-2

Yu-Jie Chen, Shur-Tzu Chen + Show 8 more

Open Access

https://doi.org/10.1038/s42003-021-02271-2

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Abstract

Metastatic cancer cells are frequently deficient in WWOX protein or express dysfunctional WWOX (designated WWOXd). Here, we determined that functional WWOX-expressing (WWOXf) cells migrate collectively and expel the individually migrating WWOXd cells. For return, WWOXd cells induces apoptosis of WWOXf cells from a remote distance. Survival of WWOXd from the cell-to-cell encounter is due to activation of the survival IκBα/ERK/WWOX signaling. Mechanistically, cell surface epitope WWOX286-299 (repl) in WWOXf repels the invading WWOXd to undergo retrograde migration. However, when epitope WWOX7-21 (gre) is exposed, WWOXf greets WWOXd to migrate forward for merge. WWOX binds membrane type II TGFβ receptor (TβRII), and TβRII IgG-pretreated WWOXf greet WWOXd to migrate forward and merge with each other. In contrast, TβRII IgG-pretreated WWOXd loses recognition by WWOXf, and WWOXf mediates apoptosis of WWOXd. The observatons suggest that normal cells can be activated to attack metastatic cancer cells. WWOXd cells are less efficient in generating Ca2+ influx and undergo non-apoptotic explosion in response to UV irradiation in room temperature. WWOXf cells exhibit bubbling cell death and Ca2+ influx effectively caused by UV or apoptotic stress. Together, membrane WWOX/TβRII complex is needed for cell-to-cell recognition, maintaining the efficacy of Ca2+ influx, and control of cell invasiveness.

Highlights

Metastatic cancer cells are frequently deficient in WWOX protein or express dysfunctional WWOX
Our study provides evidence that WWOXf cells such as normal cells have an intact system for Ca2+ influx, tend to undergo stress-regulated bubbling cell death (BCD), and repel visiting WWOXd cells via cell the surface repl epitope
In summary, we have developed new methods to distinguish the differences between WWOXf cells and WWOXd cells

Summary

Introduction

Metastatic cancer cells are frequently deficient in WWOX protein or express dysfunctional WWOX (designated WWOXd). We determined that functional WWOX-expressing (WWOXf) cells migrate collectively and expel the individually migrating WWOXd cells. WWOX7-21 peptide significantly enhances ceritinib-mediated explosion and death of 4T1 stem cell spheres[33]. PS14-WWOX strongly supports lymphocytic cell differentiation[9,37] but enhances the progression of cancer[15,16] and AD17. A majority of metastatic cancer cells are devoid of WWOX expression or possess dysfunctional WWOX protein[1,2,3,4,5,6] These cells tend to have an enhanced mobility and increased sensitivity to microenvironment[38].

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