RESUMEN
BACKGROUND: LACTB was recently identified as a mitochondrial tumour suppressor that negatively affects cancer cell proliferation by inducing cell death and/or differentiation, depending on the cell type and tissue. However, the detailed mechanism underlying the LACTB-induced cancer cell death is largely unknown. METHODS: We used cell-based, either in 2D or 3D conditions, and in vivo experiments to understand the LACTB mechanisms. In this regard, protein array followed by an enrichment analysis, cell proliferation assays using different compounds, western blot analysis, flow cytometry and immunofluorescence were performed. Differences between quantitative variables following normal distribution were valuated using Student t test for paired or no-paired samples according to the experiment. For in vivo experiments differences in tumour growth were analyzed by 2-way ANOVA. RESULTS: We show, that LACTB expression leads to cell cycle arrest in G1 phase and increase of DNA oxidation that leads to activation of intrinsic caspase-independent cell death pathway. This is achieved by an increase of mitochondrial reactive oxygen species since early time points of LACTB induction. CONCLUSION: Our work provides a deeper mechanistic insight into LACTB-mediated cancer-cell death and shows the dynamics of the cellular responses a particular tumor suppressive stimulus might evoke under different genetic landscapes.
Asunto(s)
Neoplasias de la Mama , Caspasas , Humanos , Femenino , Caspasas/genética , Caspasas/metabolismo , Apoptosis/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Puntos de Control del Ciclo Celular , Especies Reactivas de Oxígeno/metabolismo , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , Proteínas de la Membrana/genética , Proteínas Mitocondriales/genéticaRESUMEN
Epithelial-mesenchymal transition (EMT) is a cellular mechanism used by cancer cells to acquire migratory and stemness properties. In this study, we show, through in vitro, in vivo, and 3D culture experiments, that the mitochondrial protein LACTB manifests tumor suppressor properties in ovarian cancer. We show that LACTB is significantly down-regulated in epithelial ovarian cancer cells and clinical tissues. Re-expression of LACTB negatively effects the growth of cancer cells but not of non-tumorigenic cells. Mechanistically, we show that LACTB leads to differentiation of ovarian cancer cells and loss of their stemness properties, which is achieved through the inhibition of the EMT program and the LACTB-dependent down-regulation of Snail2/Slug transcription factor. This study uncovers a novel role of LACTB in ovarian cancer and proposes new ways of counteracting the oncogenic EMT program in this model system.
Asunto(s)
Transición Epitelial-Mesenquimal , Neoplasias Ováricas , Factores de Transcripción de la Familia Snail , beta-Lactamasas , Femenino , Humanos , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , Carcinogénesis , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismoRESUMEN
Tumor suppressors represent a critical line of defense against tumorigenesis. Their mechanisms of action and the pathways they are involved in provide important insights into cancer progression, vulnerabilities, and treatment options. Although nuclear and cytosolic tumor suppressors have been extensively investigated, relatively little is known about tumor suppressors localized within the mitochondria. However, recent research has begun to uncover the roles of these important proteins in suppressing tumorigenesis. Here, we review this newly developing field and summarize available information on mitochondrial tumor suppressors.