IMPDH2 mediate radioresistance and chemoresistance in osteosarcoma cells.
OBJECTIVE
Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. Despite aggressive therapy, survival outcomes remain unsatisfactory, especially for patients with metastatic disease or patients with a poor chemotherapy response. Previous study founds inosine 5'-monophosphate dehydrogenase type II (IMPDH2) was an independent prognostic factor and observed frequent IMPDH2 overexpression in osteosarcoma patients with poor response to chemotherapy. In the present work, we provide evidence for direct involvement of IMPDH2 in the development of radioresistance and chemoresistance.


METHODS
The expression of IMPDH2 was examined in OS cells. Stable cell lines overexpressing IMPDH2 and IMPDH2 knock-down cells were generated using the osteosarcoma cell line. The stable transfected cells, alone or in combination with cisplatin or γ-irradiation, was used to treat OS cells. The growth inhibitory and apoptotic effects of IMPDH2 in vitro and in vivo were examined.


RESULTS
Overexpression of IMPDH2 in IMPDH2 poor-expressed U2OS cells induced strong cisplatin chemoresistance and γ-irradiation radioresistance through inhibition of apoptosis in vitro and in vivo. Knockdown of IMPDH2 in IMPDH2 rich-expressed Saos-2 cells resulted in significant chemosensitivity and γ-irradiation radiosensitivity through inducing of apoptosis in vitro and in vivo.


CONCLUSIONS
IMPDH2 is directly involved in the development of chemoresistance and radioresistance in osteosarcoma cells, suggesting that targeting of IMPDH2 by shRNA in combination with chemotherapy and γ-irradiation might be a promising means of overcoming chemoresistance and radioresistance in osteosarcomas with high IMPDH2 expression.
Department of Hematology and Oncology, Children's Hospital of Zhengzhou, Zhengzhou, China. lihuixiazzetyy@126.com.
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Li
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Meng
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Zhang
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Bao
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Song
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Li
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005260:Female; D006801:Humans; D007168:IMP Dehydrogenase / Q000502:physiology*; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*
D007168:IMP Dehydrogenase; C501687:IMPDH2 protein, human; D002945:Cisplatin