RESUMO
Cigarette smoke-induced protein aggregation damages the lung cells in emphysema and COPD; however, lung cancer cells continue to thrive, evolving to persist in the toxic environment. Here, we showed that upon the cigarette smoke condensate exposure, A549 lung cancer cells exhibit better survival and reduced level of protein aggregation when compared to non-cancerous Beas-2B and H-6053 cells. Our data suggests that upregulation of efflux pumps in cancer cells assists in reducing smoke toxicity. Specifically, we demonstrated that inhibition of the ABCG2 transporter in A549 by febuxostat or its downregulation by shRNA-mediated RNA interference resulted in a significant increase in protein aggregation due to smoke exposure.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Fumar Cigarros , Neoplasias Pulmonares , Agregados Proteicos , Humanos , Células A549 , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismoRESUMO
Forkhead box E1 (FoxE1) protein is a transcriptional regulator known to play a major role in the development of the thyroid gland. By performing sequence alignments, we detected a deletion in FoxE1, which occurred in the evolution of mammals, near the point of divergence of placental mammals. This deletion led to the loss of the majority of the Eh1 motif, which was important for interactions with transcriptional corepressors. To investigate a potential mechanism for this deletion, we analyzed replication through the deletion area in mammalian cells with two-dimensional gel electrophoresis, and in vitro, using a primer extension reaction. We demonstrated that the area of the deletion presented an obstacle for replication in both assays. The exact position of polymerization arrest in primer extension indicated that it was most likely caused by a quadruplex DNA structure. The quadruplex structure hypothesis is also consistent with the exact borders of the deletion. The exact roles of these evolutionary changes in FoxE1 family proteins are still to be determined.