Targeting Stat3 with G-quartet oligodeoxynucleotides in human cancer cells.
Stat3 is an oncogene that is activated in many human cancer cells. Genetic approaches that disrupt Stat3 activity result in inhibition of cancer cell growth and enhanced cell apoptosis supporting the development of novel drugs targeting Stat3 for cancer therapy. G-quartet oligodeoxynucleotides (ODNs) were demonstrated to be potent inhibitors of Stat3 DNA binding activity in vitro with the G-quartet ODN, T40214, having an IC(50) of 7 microM. Computer-simulated docking studies indicated that G-quartet ODNs mainly interacted with the SH2 domain of Stat3 and were capable of inserting between the SH2 domains of Stat3 dimers bound to DNA. We demonstrated that the G-rich ODN T40214, which forms a G-quartet structure at intracellular but not extracellular K+ ion concentrations, is delivered efficiently into the cytoplasm and nucleus of cancer cells where it inhibited IL-6-stimulated Stat3 activation and suppressed Stat3-mediated upregulation of bcl-x and mcl-1 gene expression. Thus, G-quartet represents a new class of drug for targeting of Stat3 within cancer cells.
Jing
Naijie
N
Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. njing@bcm.tmc.edu
Li
Yidong
Y
Xu
Xuejun
X
Sha
Wei
W
Li
Ping
P
Feng
Lili
L
Tweardy
David J
DJ
D001483:Base Sequence; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019281:Dimerization; D018390:Gene Targeting / Q000379:methods*; D006801:Humans; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D050796:STAT3 Transcription Factor; D013489:Suppression, Genetic; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators