SERPINB3 (SCCA1) inhibits cathepsin L and lysoptosis, protecting cervical cancer cells from chemoradiation.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
12 01 2022
12 01 2022
Historique:
received:
10
02
2021
accepted:
16
11
2021
entrez:
13
1
2022
pubmed:
14
1
2022
medline:
4
3
2022
Statut:
epublish
Résumé
The endogenous lysosomal cysteine protease inhibitor SERPINB3 (squamous cell carcinoma antigen 1, SCCA1) is elevated in patients with cervical cancer and other malignancies. High serum SERPINB3 is prognostic for recurrence and death following chemoradiation therapy. Cervical cancer cells genetically lacking SERPINB3 are more sensitive to ionizing radiation (IR), suggesting this protease inhibitor plays a role in therapeutic response. Here we demonstrate that SERPINB3-deficient cells have enhanced sensitivity to IR-induced cell death. Knock out of SERPINB3 sensitizes cells to a greater extent than cisplatin, the current standard of care. IR in SERPINB3 deficient cervical carcinoma cells induces predominantly necrotic cell death, with biochemical and cellular features of lysoptosis. Rescue with wild-type SERPINB3 or a reactive site loop mutant indicates that protease inhibitory activity is required to protect cervical tumor cells from radiation-induced death. Transcriptomics analysis of primary cervix tumor samples and genetic knock out demonstrates a role for the lysosomal protease cathepsin L in radiation-induced cell death in SERPINB3 knock-out cells. These data support targeting of SERPINB3 and lysoptosis to treat radioresistant cervical cancers.
Identifiants
pubmed: 35022555
doi: 10.1038/s42003-021-02893-6
pii: 10.1038/s42003-021-02893-6
pmc: PMC8755728
doi:
Substances chimiques
Antigens, Neoplasm
0
Serpins
0
squamous cell carcinoma-related antigen
0
Cathepsin L
EC 3.4.22.15
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
46Subventions
Organisme : NCI NIH HHS
ID : K08 CA237822
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK104946
Pays : United States
Organisme : NCI NIH HHS
ID : K12 CA167540
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK114047
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA091842
Pays : United States
Informations de copyright
© 2022. The Author(s).
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