MEPE/OF45 as a new target for sensitizing human tumour cells to DNA damage inducers.

Matrix extracellular phosphoglycoprotein/osteoblast factor 45 (MEPE/OF45) was originally cloned from a human oncogenetic hypophosphataemia tumour (Rowe et al, 2000) and then identified in rat bone-marrow-derived osteoblasts (Petersen et al, 2000). The murine homologue of MEPE/OF45 was reported the following year (Argiro et al, 2001). Since the identification of MEPE/OF45, its function related to bone metabolism has been widely investigated. We previously identified that MEPE/OF45, as a cofactor of CHK1, protects cells from DNA damage-induced killing in rat embryo fibroblast cells (Liu et al, 2009). However, because human MEPE/OF45 (hMEPE/OF45) has only ∼50% homology with rat MEPE/OF45 (rMEPE/OF45), it remained unclear whether hMEPE/OF45 has similar function to rMEPE/OF45. CHK1 is one of the essential checkpoint proteins involved in cellular response to multiple DNA damage inducers (Liu et al, 2000; Zhao et al, 2002). It is believed that upregulated CHK1 protects cells from DNA damage-induced cell killing, including that induced by ionising radiation (IR) and camptothecin (CPT) (Hu et al, 2001, 2005a; Zhao et al, 2002; Wang et al, 2002b; Brown and Baltimore, 2003), by promoting homologous recombination repair (HRR) (Sorensen et al, 2005; Hu et al, 2005b). Despite the importance of CHK1 in DNA damage response, the regulation of CHK1 in mammalian cells is not well understood, partly because of its essential nature (Liu et al, 2000; Lam et al, 2004). In this study, on the basis of our previous report about the new role of rMEPE/OF45 in protecting cells from DNA damage-induced killing (Liu et al, 2009), we investigate whether hMEPE/OF45 is generally expressed in different types of tumour cells, whether the expression levels were relevant to the resistance of tumour cells to DNA damage inducers and whether, similar to rMEPE/OF45, hMEPE/OF45 (as a cofactor of CHK1) could be a new target for sensitizing human tumour cells to DNA damage inducers.