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 approximately 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.


CONCLUSIONS
hMEPE/OF45 could be a new target for sensitizing tumour cells to radiotherapy or chemotherapy.
Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
P
P
Zhang
H
H
Wang
P S N
PS
Rowe
B
B
Hu
Y
Y
Wang
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000528:radiation effects*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D010750:Phosphoproteins / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D051381:Rats
D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C486579:MEPE protein, human; D010750:Phosphoproteins; D011838:Radiation-Sensitizing Agents; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605871:Chek1 protein, rat; D002166:Camptothecin