CST1 promotes the metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer

Cysteine Protease Inhibitor 1 (CST1), a cystatin superfamily protein with the effect on the inhibition of cysteine protease activity , is reported to be involved in the development of many malignancies. Mitochondrial oxidative phosphorylation (OXPHOS) also plays an important role on regulating cancer cell growth. However, the relationship and role of CST1 and OXPHOS on esophageal squamous cell carcinoma (ESCC) remains unknown. In our pilot study, CST1 was shown the potential of promoting ESCC migration and invasion by the activation of MEK/ERK pathway. Especially mentioned, we found that CST1 is closely associated with OXPHOS by the analysis of transcriptome sequencing. And then, based on real-time ATP rate assay, mitochondrial complex I enzyme activity assay, immunofluorescence (IF), co-immunoprecipitation (CO-IP), and additions of OXPHOS inhibitor Rotenone and MEK/ERK inhibitor PD98059, we defined the effect of CST1 on mitochondrial complex I enzyme activity by interacting with GRIM19 protein to elevate OXPHOS levels, and the reciprocal regulatory relationship existed between OXPHOS and MEK/ERK pathway in ESCC cells. Finally, a study in vivo well demonstrated the potential of CST1 on ESCC metastasis by the regulation of OXPHOS and MEK/ERK pathway. This study is the first to unveil the oncogenic role of CST1 on ESCC development by enhancing mitochondrial respiratory chain complex I activity to activate an OXPHOS/MEK/ERK axis, and then promote ESCC metastasis, suggesting that CST1/OXPHOS might be a promising target for ESCC treatment.