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Resveratrol suppresses tumorigenicity and enhances radiosensitivity in primary glioblastoma tumor initiating cells by inhibiting the STAT3 axis
Author(s) -
Yang YiPing,
Chang YuhLih,
Huang PinI,
Chiou GuangYuh,
Tseng LingMing,
Chiou ShihHwa,
Chen MingHsiung,
Chen MingTeh,
Shih YangHsin,
Chang ChinHong,
Hsu ChuanChih,
Ma HsinI,
Wang ChinTien,
Tsai LoLin,
Yu ChengChia,
Chang CharnJung
Publication year - 2012
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22806
Subject(s) - radioresistance , radiosensitivity , cancer research , stat3 , in vivo , apoptosis , resveratrol , glioma , cancer stem cell , small hairpin rna , biology , cancer , medicine , radiation therapy , pharmacology , gene knockdown , biochemistry , microbiology and biotechnology
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. J. Cell. Physiol. 227: 976–993, 2012. © 2011 Wiley Periodicals, Inc.