STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells.
Signal transducer and activator of transcription 3 (STAT3) regulates diverse cellular processes, including cell growth, differentiation, and apoptosis, and is frequently activated during tumorigenesis. Recently, putative glioblastoma stem cells (GBM-SCs) were isolated and characterized. These cells can self-renew indefinitely in culture, are highly tumorigenic, and retain the ability to differentiate in culture. We have found that treatment of GBM-SCs with two chemically distinct small molecule inhibitors of STAT3 DNA-binding inhibits cell proliferation and the formation of new neurospheres from single cells. Genetic knockdown of STAT3 using a short hairpin RNA also inhibits GBM-SC proliferation and neurosphere formation, confirming that these effects are specific to STAT3. Although STAT3 inhibition can induce apoptosis in serum-derived GBM cell lines, this effect was not observed in GBM-SCs grown in stem cell medium. Markers of neural stem cell multipotency also decrease upon STAT3 inhibition, suggesting that STAT3 is required for maintenance of the stem-like characteristics of these cells. Strikingly, even a transient inhibition of STAT3 leads to irreversible growth arrest and inhibition of neurosphere formation. These data suggest that STAT3 regulates the growth and self-renewal of GBM-SCs and is thus a potential target for cancer stem cell-directed therapy of glioblastoma multiforme.
Sherry
Maureen M
MM
Department of Physiology, Tufts University, Boston, Massachusetts 02111, USA.
Reeves
Andrew
A
Wu
Julian K
JK
Cochran
Brent H
BH
D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003470:Culture Media / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006131:Growth Inhibitors / Q000378:metabolism; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000494:pharmacology; D008297:Male; D039902:Multipotent Stem Cells / Q000187:drug effects / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism
D003470:Culture Media; D006131:Growth Inhibitors; D051798:Inhibitor of Differentiation Protein 1; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human