A Long-Range Foresight for the Medical Application of Apoptosis Specifically Induced by Dd-MRP4, Dictyostelium Mitochondrial Ribosomal Protein S4, to Cancer Therapy

Abstract

Apoptosis (programmed cell death) is regarded as ultimate differentiation of the cell. We have recently demonstrated that a targeted delivery of Dd-MRP4 (Dictyostelium mitochondrial ribosomal protein S4) suppresses specifically the proliferation of the human cancer cells, by inducing their apoptotic cell death (Chida et al., 2014, doi:10.1186/1475-2867-14-56). This amazing fact was discovered, simply based on the finding that Dd-MRP4 expression is absolutely required for transition of Dictyostelium cells from growth to differentiation (Chida et al., 2008, doi:10.1186/1471-2156-9-25; Maeda et al., 2013, doi:10.3390/biom3040943). Dd-MRP4 protein has quite unique structural characters, in that it is highly basic (pI: about 11.5) and interestingly has several nuclear-localization signals within the molecule. In this review, we introduce briefly the efficacy of several apoptosis-inducing substances reported thus far for cancer therapy, and speculate the possible mechanisms, by which apoptosis is specifically induced by Dd-MRP4, on the basis of its structural uniqueness. We also discuss several issues to be solved for the medical application of ectopically expressed Dd-MRP4 in human cancer cells.

Mitochondrial ribosomes in cancer

“…However, contrasting evidence has suggested a role for DAP3 in the mitochondrial apoptotic pathway and indicated DAP3-independent Fas-induced and TRAIL (tumor necrosis factor-related apoptosis inducing ligand)-induced apoptosis [92–94]. Moreover, mS29/DAP3 induces mitochondria-mediated apoptosis of a human laryngeal carcinoma cell line (Hep2 cells) through the activation of p38 MAPK and JNK signaling [95, 96]. The intrinsic pro-apoptotic role of DAP3 is further highlighted by the fact that overexpression of human, mouse or yeast DAP3 leads to cell death resulting in mitochondrial fragmentation, perhaps affecting mitochondrial fission [94, 97] in a manner dependent on the GTP-binding ability of DAP3 and its mitochondrial localization [94].…”