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

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 great...

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Published in:Cell death & disease 2022-06, Vol.13 (6), p.532-12, Article 532
Main Authors: Zhang, Cheng, Ma, Hong-Ming, Dong, Shuang-Shu, Zhang, Na, He, Ping, Ge, Meng-Kai, Xia, Li, Yu, Jian-Xiu, Xia, Qiang, Chen, Guo-Qiang, Shen, Shao-Ming
Format: Article
Language:English
Subjects:
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Antibodies
Biochemistry
Biomedical and Life Sciences
Cancer
Carcinogenesis
Cell Biology
Cell Culture
Chromosome 10
Furin
Furin - genetics
Humans
Immunology
Life Sciences
Liver cancer
Liver Neoplasms
Proprotein Convertases
PTEN protein
Resistant mutant
Tensin
Tumors
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Summary: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.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-022-04988-2