Inhibition of RNA transportation induces glioma cell apoptosis via downregulation of RanGAP1 expression.
The prognosis of glioblastoma remains poor, even treatment with surgery, radiation, or chemotherapy. Therefore, it is still important to develop a new strategy for treatment of glioblastoma. Previous reports demonstrated that rRNA is produced at abnormally high levels in tumor cells. Nuclear export of all non-coding RNAs are known to depend on RanGTPase system. Hydrolyzation of RanGTP-RNA complex by RanGTPase activating protein 1 (RanGAP1) releases RNA from nucleus to cytoplasm. Therefore, inhibition of RNA transportation would be a useful strategy to affect cancer cell fate. In this study, 5-30 μM of oridonin, a natural diterpenoid compound isolated from the traditional Chinese medicine, Rabdosia rubescens, induced U87MG glioma cell apoptosis and RNA accumulation in nucleus at 12h-time point. Before U87MG cell apoptosis, the RanGAP1 protein amount decreased and RanGTP accumulated in nucleus as respectively determined by immunoprecipitation and immunofluorescence, suggesting that decrease of RanGAP1 may result in nuclear entrapment of RanGTP and RNA, and then induce U87MG cell death. In contrast, over-expression of the RanGAP1 protein reversed oridonin-induced U87MG cell apoptosis. Hence, we demonstrated that downregulation of the RanGAP1 protein level by oridonin may result in RNA accumulation in nucleus via nuclear entrapment of RanGTP which eventually led to the apoptosis of glioma cells.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Biochemistry, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Tsung-Yao
TY
Lin
Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan.
Chin-Cheng
CC
Lee
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Biochemistry, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Ku-Chung
KC
Chen
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Biochemistry, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Chien-Ju
CJ
Lin
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Biochemistry, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. Electronic address: cmshih@tmu.edu.tw.
Chwen-Ming
CM
Shih
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D012313:RNA / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D045786:Diterpenes, Kaurane; D020690:GTPase-Activating Proteins; C092317:RANGAP1 protein, human; C011959:oridonin; D012313:RNA
Apoptosis; Oridonin; RNA transportation; RanGAP1; RanGTP; U87MG cells