Effect of MPS1 Inhibition on Genotoxic Stress Responses in Murine Tumour Cells.
OBJECTIVE
The monopolar spindle 1 (MPS1) is a serine/threonine kinase that plays an important role in spindle assembly checkpoint signaling. To determine the possible relationship between MPS1 inhibition and genotoxic stress responses, herein we examined whether MPS1 inhibition influences cellular susceptibility towards two genotoxic treatments, etoposide and ionizing radiation (IR).


METHODS
Two murine tumour cell lines, SCCVII and EMT6, were used. The effect of genotoxic treatments with or without two novel MPS1 inhibitors, NMS-P715 and AZ3146, on cellular survival, cell-cycle distribution, centrosome status and mitotic catastrophe (MC) was evaluated.


RESULTS
MPS1 inhibition sensitized murine tumour cells to etoposide but not to IR. In addition, MPS1 inhibition altered cell-cycle progression and exacerbated centrosome abnormalities, resulting in enhanced MC induced by etoposide but not by IR.


CONCLUSIONS
MPS1 inhibition promotes the etoposide-induced aberrant mitosis and, consequently, the induction of tumour cell death.
Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Motofumi
M
Suzuki
Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan yamamorit@vetmed.hokudai.ac.jp inanami@vetmed.hokudai.ac.jp.
Tohru
T
Yamamori
Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Hironobu
H
Yasui
Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan yamamorit@vetmed.hokudai.ac.jp inanami@vetmed.hokudai.ac.jp.
Osamu
O
Inanami
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018385:Centrosome; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D005047:Etoposide; C441620:Ttk protein, mouse; D017346:Protein Serine-Threonine Kinases
MPS1; cell death; centrosome amplification; etoposide; mitotic catastrophe