Pterostilbene suppressed irradiation-resistant glioma stem cells by modulating GRP78/miR-205 axis.
Glioblastoma multiforme (GBM) is the most aggressive type characterized by relapse and resistance even with the combination of radio- and chemotherapy. The presence of glioma stem cells (GSCs) has been shown to contribute to tumorigenesis, recurrence and treatment resistance. Particularly, CD133-positive glioma cells have been shown to represent the subpopulation that confers glioma radioresistance and suggested to be the source of tumor recurrence after radiation. Thus, a better understanding and the development of agents which target GSCs could potentially lead to a significant improvement in treating GBM patients. Here, we demonstrated that GRP78 (an antistress protein) was highly expressed in GBM cells along with β-catenin and Notch and correlated to the development of GSCs. CD133+ GSCs exhibited enhanced migration/invasion and self-renewal abilities. When GRP78 was silenced, GSC properties were suppressed and the sensitivity towards irradiation increased. In addition, the level of microRNA 205 appeared to be negatively associated with GRP78 expression. Our previous study indicated that pterostilbene (PT) possessed anticancer stem cell properties in hepatocellular carcinoma. Thus, we examined whether PT is also effective against GSCs. We found that PT-treated GSCs exhibited suppressed self-renewal and irradiation-resistant abilities. PT-mediated effects were associated with an increase of miR-205. Finally, we showed that PT treatment suppressed tumorigenesis in GSC xenograft mice. In conclusion, we provided evidence that GRP78/miR-205 axis played an important role in GSC maintenance and irradiation resistance. PT treatment suppressed GSC development via negatively modulating GRP78 signaling. PT may be considered for combined therapeutic agent to enhance irradiation efficacy in GBM patients.
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam.
Thanh-Tuan
TT
Huynh
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
Chien-Min
CM
Lin
Department of Pathology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
Wei-Hwa
WH
Lee
Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Alexander T H
AT
Wu
Biostatistics and Research Consultation Center, Taipei Medical University, Taipei, Taiwan.
Yen-Kuang
YK
Lin
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Yuh-Feng
YF
Lin
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Medical Research and Education, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan. Electronic address: ctyeh@s.tmu.edu.tw.
Chi-Tai
CT
Yeh
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Thoracic Surgery, Department of Surgery, Taipei Medical University- Shuang Ho Hospital, Taipei, Taiwan. Electronic address: wangls72269@yahoo.com.tw.
Liang-Shun
LS
Wang
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006360:Heat-Shock Proteins / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D035721:Pterocarpus / Q000737:chemistry; D011836:Radiation Tolerance; D013267:Stilbenes / Q000302:isolation & purification / Q000494:pharmacology*
D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D035683:MicroRNAs; D013267:Stilbenes; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; C534425:MIR205, human; C107773:pterostilbene
CD133+ glioma stem cells; Glucose-regulated protein, 78 kDa (GRP78); Irradiation resistance; Pterostilbene; miR-205