Professor National Cheng Kung University, Taiwan (Republic of China)
Nan-Shan Chang (National Cheng Kung University)| Yu-An Chen (National Cheng Kung University)| Yong-Da Sie (National Cheng Kung University)| Tsung-Yun Liu (National Cheng Kung University)| Hsiang-Ling Kuo (National Cheng Kung University)| Pei-Yi Chou (National Cheng Kung University)| Yu-Jie Chen (National Cheng Kung University)| Kuan-Ting Lee (National Cheng Kung University)
Metastatic cancer cells frequently express dysfunctional WWOX or are deficient in WWOX protein (designated as WWOXd). Here, we determined that WWOXd cells are less efficient in generating Ca2+ influx and undergo non-apoptotic explosion in response to UV or stress stimuli at room temperature, and migrate individually. Functional WWOX-expressing cells (WWOXf) exhibit Ca2+influx effectively, migrate collectively, and undergo bubbling cell death (BCD) under stress stimuli. WWOXf cells expel visiting WWOXd cells, and WWOXd induces apoptosis of WWOXf from a distance. Mechanistically, a complex of WWOX and type II TGFb receptor (TbRII) in the lipid raft is involved in cell-to-cell recognition. We determined that surface epitope WWOX286-299 (repl) in WWOXf cells repels the invading WWOXd cells. In contrast, epitope WWOX7-21 (gre) enables WWOXd cells to undergo anterograde migration for merge with WWOXf cells, without causing apoptosis. Suppression of TbRII in WWOXf cells by antibody leads to enhanced migration of WWOXd cells to the WWOXf cells for merge. In contrast, when WWOXd cells are pretreated with TbRII or pY33-WWOX antibody, they lose recognition by WWOXf and are subjected to WWOXf-mediated apoptosis. Together, membrane WWOX/TbRII complex participates in cell-to-cell recognition. Loss of membrane localized WWOX and reduced efficacy in Ca2+ influx contribute, in part, to increased cancer cell individual migration and metastasis.