SERPINB3 (SCCA1) inhibits cathepsin L and lysoptosis, protecting cervical cancer cells from chemoradiation

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. Wang et al. demonstrate the cytoprotective role of SERPINB3 against radiation-induced necrosis, showing that cells lacking SERPINB3 protein both in culture and in mice are more sensitive to radiation and cisplatin-induced cell death. The authors also report that the cell death induced by radiation in SERPINB3-lacking cells is lysoptosis and implicate the lysosomal protease cathepsin L in this process.

Automated summary

This study demonstrates that cells lacking SERPINB3 have enhanced sensitivity to radiation-induced cell death, even more so than cisplatin. The cell death induced by radiation in SERPINB3-deficient cervical carcinoma cells is predominantly lysoptosis, and the lysosomal protease cathepsin L is implicated in this process.