RESUMEN
Metastasis is the leading cause of mortality in patients with solid tumors. In this regard, we previously reported that Pseudopodium-Enriched Atypical Kinase One (PEAK1) is necessary for non-canonical Transforming Growth Factor ß (TGFß) signaling and TGFß/fibronectin-induced metastasis. Here, we demonstrate that inhibition of DHPS-dependent eIF5A1/2 hypusination blocks PEAK1 and E-Cadherin expression, breast cancer cell viability and TGFß/fibronectin-induced PEAK1-dependent breast cancer metastasis. Interestingly, TGFß stimulation of high-grade metastatic breast cancer cells increases and sustains eIF5A1/2 hypusination. We used a suite of bioinformatics platforms to search biochemical/functional interactions and clinical databases for additional control points in eIF5A1/2 and PEAK1-Epithelial to Mesenchymal Transition (EPE) pathways. This effort revealed that interacting EPE genes were enriched for TP53 transcriptional targets and were commonly co-amplified in breast cancer patients harboring inactivating TP53 mutations. Taken together, these results suggest that combinatorial therapies targeting DHPS and protein activities elevated in TP53-mutant breast cancers may reduce systemic tumor burden and improve patient outcomes.
Asunto(s)
Neoplasias de la Mama/metabolismo , Fibronectinas/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Factores de Iniciación de Péptidos/metabolismo , Proteínas de Unión al ARN/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Proteína p53 Supresora de Tumor/genética , Neoplasias de la Mama/patología , Cadherinas/antagonistas & inhibidores , Cadherinas/genética , Cadherinas/metabolismo , Femenino , Guanina/análogos & derivados , Guanina/farmacología , Humanos , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/antagonistas & inhibidores , Factores de Iniciación de Péptidos/antagonistas & inhibidores , Pronóstico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Proteínas de Unión al ARN/antagonistas & inhibidores , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/metabolismo , Factor 5A Eucariótico de Iniciación de TraducciónRESUMEN
The cultivation of normal mouse spleen cells in a modified Mishell-Dutton system for 1-4 days in the presence of a water-soluble antigen of sheep red blood cells results in a sharp increase in the number of cells secreting non-specific immunoglobulins (nIFC). This increase is much more visible if spleen cells from mice primed with the same antigen 3-4 days before cultivation, are used. The rise in NIFC becomes apparent on day 1 and runs up to maximum on day 3. At this time a peak of 165 X 10(3) nIFC per 10(6) cells is attained, i.e. the nIFC quantity reaches approximately 33% of total B-cells. Kinetics of the antibody-forming cells and nIFC appearance under varying conditions is different. Clearcut differences are also revealed between the mechanisms of regulation of both these populations. The initial population of cells destined to form non-specific immunoglobulin is estimated to be 363/10(6) cells during a primary immune response in vitro; if splenocyte donors are primed with a homologous antigen, this population become approximately 800-1,900/10(6) cells.
