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

BACKGROUND: We recently identified matrix extracellular phosphoglycoprotein/osteoblast factor 45 (MEPE/OF45) as a new cofactor of CHK1 in rat cells. The aim of this study was to determine the role of human MEPE/OF45 (hMEPE/OF45 has ∼50% homology with rat MEPE/OF45 (rMEPE/OF45)) in affecting the sensitivity of human tumour cells to DNA damage. METHODS: hMEPE/OF45 expression in different human tumour cell lines and its relevance to the resistance of cell lines to DNA damage inducers such as ionising radiation (IR) or camptothecin (CPT) were assessed. Cells lines stably expressing wild-type MEPE/OF45 or mutant MEPE/OF45 (with the CHK1 interactive key domain (amino acids 488–507) deleted) were established. Cell survival, G(2) accumulation, CHK1 half-life and the CHK1 level in ligase 3 complexes were examined. RESULTS: hMEPE/OF45 expression correlates with the resistance of cell lines to IR or CPT. Upregulating wild-type hMEPE/OF45 (but not mutant hMEPE/OF45) could stabilize CHK1 by reducing CHK1 interaction for its E3 ligases Cul1 or Cula4A; it increases the G(2) checkpoint response and increases the resistance of tumour cells to IR or CPT treatment. CONCLUSION: hMEPE/OF45 could be a new target for sensitizing tumour cells to radiotherapy or chemotherapy.