title: Resveratrol suppresses tumorigenicity and enhances radiosensitivity in primary glioblastoma tumor initiating cells by inhibiting the STAT3 axis.
abstract: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Patients diagnosed with GBM have a poor prognosis, and it has been reported that tumor malignancy and GBM recurrence are promoted by STAT3 signaling. As resveratrol (RV), a polyphenol in grapes, is reported to be a potent and non-toxic cancer-preventive compound, the aim of this study was to investigate the therapeutic effect and molecular mechanisms of RV on GBM-derived radioresistant tumor initiating cells (TIC). Firstly, our results showed that primary GBM-CD133(+) TIC presented high tumorigenic and radiochemoresistant properties as well as increased protein levels of phosphorylated STAT3. We consistently observed that treatment with shRNA-STAT3 (sh-STAT3) or AG490, a STAT3 inhibitor, significantly inhibited the cancer stem-like cell properties and radioresistance of GBM-CD133(+) in vitro and in vivo. Furthermore, treatment of GBM-CD133(+) with 100 µM RV induced apoptosis and enhanced radiosensitivity by suppressing STAT3 signaling. Microarray results suggested that RV or AG490 inhibited the stemness gene signatures of GBM-CD133(+) and facilitated the differentiation of GBM-CD133(+) into GBM-CD133(-) or astrocytoma cells. Finally, xenotransplant experiments indicated that RV or sh-STAT3 therapy could significantly improve the survival rate and synergistically enhance the radiosensitivity of radiation-treated GBM-TIC. In summary, RV can reduce in vivo tumorigenicity and enhance the sensitivity of GBM-TIC to radiotherapies through the STAT3 pathway.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Yang
authors.forename: Yuh-Lih
authors.initials: YL
authors.lastname: Chang
authors.forename: Pin-I
authors.initials: PI
authors.lastname: Huang
authors.forename: Guang-Yuh
authors.initials: GY
authors.lastname: Chiou
authors.forename: Ling-Ming
authors.initials: LM
authors.lastname: Tseng
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.forename: Ming-Hsiung
authors.initials: MH
authors.lastname: Chen
authors.forename: Ming-Teh
authors.initials: MT
authors.lastname: Chen
authors.forename: Yang-Hsin
authors.initials: YH
authors.lastname: Shih
authors.forename: Chin-Hong
authors.initials: CH
authors.lastname: Chang
authors.forename: Chuan-Chih
authors.initials: CC
authors.lastname: Hsu
authors.forename: Hsin-I
authors.initials: HI
authors.lastname: Ma
authors.forename: Chin-Tien
authors.initials: CT
authors.lastname: Wang
authors.forename: Lo-Lin
authors.initials: LL
authors.lastname: Tsai
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
authors.forename: Charn-Jung
authors.initials: CJ
authors.lastname: Chang
mesh_terms: D000368:Aged; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001254:Astrocytoma / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D059248:Chemoradiotherapy / Q000379:methods; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D000077185:Resveratrol; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013267:Stilbenes; D000077185:Resveratrol