ZDHHC8 knockdown enhances radiosensitivity and suppresses tumor growth in a mesothelioma mouse model.
Mesothelioma is an aggressive tumor caused by asbestos exposure, the incidence of which is predicted to increase globally. The prognosis of patients with mesothelioma undergoing conventional therapy is poor. Radiation therapy for mesothelioma is of limited use because of the intrinsic radioresistance of tumor cells compared with surrounding normal tissue. Thus, a novel molecular-targeted radiosensitizing agent that enhances the radiosensitivity of mesothelioma cells is required to improve the therapeutic efficacy of radiation therapy. ZDHHC8 knockdown reduces cell survival and induces an impaired G(2) /M checkpoint after X-irradiation in HEK293 cells. In the present study, we further analyzed the effect of the combination of ZDHHC8 knockdown and X-irradiation and assessed its therapeutic efficacy in mesothelioma models. SiRNA-induced ZDHHC8 knockdown in 211H and H2052 mesothelioma cells significantly reduced cell survival after X-irradiation. In 211H cells treated with ZDHHC8 siRNA and X-irradiation, the G(2) /M checkpoint was impaired and there was an increase in the number of cells with micronuclei, as well as apoptotic cells, in vitro. In 211H tumor-bearing mice, ZDHHC8 siRNA and X-irradiation significantly suppressed tumor growth, whereas ZDHHC8 siRNA alone did not. Immunohistochemical analysis showed decreased cell proliferation and induction of apoptosis in tumors treated with ZDHHC8 siRNA and X-irradiation, but not with ZDHHC8 siRNA alone. These results suggest that ZDHHC8 knockdown with X-irradiation induces chromosomal instability and apoptosis through the impaired G(2) /M checkpoint. In conclusion, the combination of ZDHHC8 siRNA and X-irradiation has the potential to improve the therapeutic efficacy of radiation therapy for malignant mesothelioma.
Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan. h_sudo@nirs.go.jp
Hitomi
H
Sudo
Atsushi B
AB
Tsuji
Aya
A
Sugyo
Yuriko
Y
Ogawa
Masashi
M
Sagara
Tsuneo
T
Saga
D000217:Acyltransferases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000528:radiation effects; D043171:Chromosomal Instability; D004195:Disease Models, Animal; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008654:Mesothelioma / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology; D011836:Radiation Tolerance; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D008565:Membrane Proteins; D034741:RNA, Small Interfering; D000217:Acyltransferases; C488097:ZDHHC8 protein, human