Abstract
Background: Understanding how cells respond to mitotic poisons is of great biomedical and clinical significance. However, it remains unknown how cell-death or survival is determined during exposure to anti-mitotic drugs. Methods: The biological effects of LIV-1 and GRPEL1 on mitotic exit and apoptosis were evaluated both in vitro and in vivo using flow cytometry, western blotting, xenografts and time-lapse imaging. The interactions between proteins and the ubiquitination of GRPEL1 were assessed by GST pull down, immunoprecipitation and mass spectrometry analysis. The expression of LIV-1 in cancers was assessed by immunohistochemistry. Findings: Overexpression of LIV-1 led to direct apoptosis. Depleted for LIV-1 evade anti-mitotic agent-induced killing through a rapid exit from arrested mitosis. LIV-1 interacts with GRPEL1 and Stabilizes GRPEL1 Protein by Preventing Ubiquitylation of GRPEL1. LIV-1-GRPEL1 axis regulate mitotic exit through inhibiting PP2A-B55I± phosphates activity, and promot apoptosis partially through the release of AIF. Loss of function in this axis was frequent in multiple types of human epithelial cancer. Interpretation: These data demonstrate that LIV-1-GRPEL1 axis dually regulates mitotic exit as well as apoptosis by interacting with PP2A B55I± and AIF. Its discovery constitutes a conceptual advance for the decisive mechanism of cell fate during damaged mitosis. Funding Statement: National Clinical Research Center for Obstetric and Gynecologic Diseases, the National Natural Science Foundation of China. Declaration of Interests: The authors declare that there are no conflicts of interest with this work. Ethical Approval Statement: All animals were obtained from BEIJING HFK BIOSCIENCE Co., Ltd. (Beijing, China), and experiments were approved by the Committee on the Ethics of Animal Experiments of Tongji Medical College. Mice were maintained in the accredited animal facility of Tongji Medical College.
Published Version
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