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Background  In general, growth and differentiation are mutually exclusive but are cooperatively regulated throughout development. Thus, the process of a cell’s switching from growth to differentiation is of great importance not only for the development of organisms but also for malignant transformation, in which this process is reversed. We have previously demonstrated using a  Dictyostelium  model system that the  Dictyostelium  mitochondrial ribosomal protein S4 ( Dd-mrp4 ) gene expression is essential for the initiation of cell differentiation:  Dd-mrp4 -null cells fail to initiate differentiation, while the initial step of cell differentiation and the subsequent morphogenesis are markedly enhanced in  mrp4  OE  cells overexpressing the  Dd-mrp4  in the extramitochondrial cytoplasm. This raised a possibility that the ectopically enforced expression of the  Dd-mrp4  in human cells might inhibit their growth, particularly of malignant tumor cells, by inducing cell differentiation.    Methods  Four kinds of human tumor cell lines were transfected by three kind of vector constructs (the empty vector: pcDNA3.1 (Mock); pcDNA3.1- rps4  bearing  Dictyostelium  cytoplasmic ribosomal protein S4; pcDNA3.1- mrp4  bearing  Dictyostelium  mitochondrial ribosomal protein S4). As controls, four kinds of human primary cultured cells were similarly transfected by the above vector constructs. After transfection, growth kinetics of cells was analyzed using cell viability assay, and also the TUNEL method was used for evaluation of apoptotic cells.    Results  Ectopically expressed  Dd-mrp4  suppressed cell proliferation through inducing apoptotic cell death specifically in the human lung adenocarcinoma (A549), epithelial cervical cancer (HeLa), hepatocellular carcinoma (HepG2) and colonic carcinoma (Caco-2), but not in primary cultured normal cells, such as human brain microvascular endothelial cells (HBMECs); human umbilical vein endothelial cells (HUVECs) and human normal hepatocytes (hHeps™), with one exception (human cardiac fibloblasts (HCF)).    Conclusion  The present finding that the ectopically enforced expression of  Dd-mrp4  in human several tumor cell lines specifically suppresses their proliferation suggests strongly that the  Dd-mrp4  gene derived from  Dictyostelium  mitochondria may provide a new promising therapeutic strategy for disrupting cell viability pathways in human cancers.

Specific growth suppression of human cancer cells by targeted delivery of Dictyostelium mitochondrial ribosomal protein S4