Furin extracellularly cleaves secreted PTENα/β to generate C-terminal fragment with a tumor-suppressive role.

Abstract

PTENα and PTENβ (PTENα/β), two long translational variants of phosphatase and tensin homolog on chromosome 10 (PTEN), exert distinct roles from canonical PTEN, including promoting carcinogenesis and accelerating immune-resistant cancer progression. However, their roles in carcinogenesis remain greatly unknown. Herein, we report that, after secreting into the extracellular space, PTENα/β proteins are efficiently cleaved into a short N-terminal and a long C-terminal fragment by the proprotein convertase Furin at a polyarginine stretch in their N-terminal extensions. Although secreted PTENα/β and their cleaved fragment cannot enter cells, treatment of the purified C-terminal fragment but not cleavage-resistant mutants of PTENα exerts a tumor-suppressive role in vivo. As a result, overexpression of cleavage-resistant PTENα mutants manifest a tumor-promoting role more profound than that of wild-type PTENα. In line with these, the C-terminal fragment is significantly downregulated in liver cancer tissues compared to paired normal tissues, which is consistent with the downregulated expression of Furin. Collectively, we show that extracellular PTENα/β present opposite effects on carcinogenesis from intracellular PTENα/β, and propose that the tumor-suppressive C-terminal fragment of PTENα/β might be used as exogenous agent to treat cancer.

• Authors: Cheng Zhang, Hong-Ming Ma, Shuang-Shu Dong, Na Zhang, Ping He, Meng-Kai Ge, Li Xia, Jian-Xiu Yu, Qiang Xia, Guo-Qiang Chen, Shao-Ming Shen
• Journal: Cell death & disease (Cell Death Dis) Vol. 13 Issue 6 Pg. 532 (06 06 2022) ISSN: 2041-4889 [Electronic] England
• PMID: 35668069 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Proprotein Convertases
• Furin

Topics

• Carcinogenesis
• Furin (genetics)
• Humans
• Liver Neoplasms
• Proprotein Convertases