Blockage of the STAT3 signaling pathway with a decoy oligonucleotide suppresses growth of human malignant glioma cells

Abstract

Gliomas are the most common type of primary tumor in the human central nervous system. STAT3, a signal transducer and activator of transcription 3, is over expressed in gliomas. Its involvement in tumorgenesis can be attributed to its ability to induce cell proliferation and inhibit apoptosis. Double-stranded decoy oligodeoxynucleotides (ODNs) which correspond closely to the STAT3 response element within the c-fos promoter are a potential tool for inhibiting a variety of tumor cell growth. To investigate its therapeutic potential in malignant gliomas, a 15-mer double-stranded decoy ODN mimicking STAT3-specific cis-elements was transfected into two glioma cell lines, U251 and A172. The STAT3 decoy ODN treatment specifically blocked STAT3 signaling and subsequently inhibited U251 and A172 cell proliferation by inducing apoptosis and cell-cycle arrest. The ODN treatment also decreased transcription and translation of downstream STAT3 target genes including c-myc, cyclin D1 and bcl-xl in both cell lines. Thus, targeted blockade of the STAT3 signaling pathway with a decoy ODN is a potential anti-glioma therapeutic approach.

Signal transducer and activator of transcription 1 (Stat1) maintains basal mRNA expression of pro-survival stat3-target genes in glioma C6 cells

“…Our results obtained in C6 glioma cells with Stat3 decoy are in apparent disagreement with the results obtained by Gu et al [2008] in two glioma cell lines: U251 and A172. Upon transfecting those cells with the same Stat3 decoy, the authors observed downregulation of Bcl2l1, Myc, and Ccnd1, as well as decreased cell viability.…”

Down-Regulation of Stat3 Decreases Invasion Activity and Induces Apoptosis of Human Glioma Cells

“…Primers used to detect Stat3 expression were 5′-GGGTCTGGCTAGACAATAT (Gu et al 2008); survivin, 5′-TTGGCAGGTGCCTGTTGAAT -3′ and 5′-AGC CAGTCCCCCACAGCAT -3′ (Shinozawa et al 2000); MMP-2, 5′-GTGCTGAAGGACACACTAAAGAAGA -3′ and 5′-TTGCCATCCTTCTCAAAGTTGTAGG -3′ ; and primers against β-actin as a positive control were 5′-CCAAGGCCAACCGCGAGAAGATGAC -3′ and 5′-AGGGTACATGGTGGTGCCGCCAGAC -3′. After amplification, polymerase chain reaction products were electrophoresed on a 1% agarose gel and visualized by ethidium bromide staining.…”

“…Previous studies have demonstrated that blockade of Stat3 signaling induces cell apoptosis (Konnikova et al 2003;Gao et al 2005;Nam et al 2005;Gu et al 2008;Ren et al 2008). Annexin V Assay was used to examine the apoptosis cells after transfecting Stat3 shRNA.…”

Disruption of Protein–DNA Interactions: An Opportunity for Cancer Chemotherapy

“…Galiellalactone (Weidler et al, 2000;Hellsten et al, 2008), flavopiridol (Lee et al, 2006) and a class of platinum (IV) compounds including IS3295 (Turkson et al, 2005), CPA-1, CPA-7 and platinum (V) tetrachloride (Turkson et al, 2004b), and decoy oligodeoxynucleotides (Xi et al, 2005;Zhang et al, 2007;Gu et al, 2008;Sun et al, 2008;Zhang et al, 2010;Barton et al, 2004) were found to interfere with Stat3 binding to DNA as well as induce cell growth inhibition and apoptosis of human breast, lung and prostate cancer cells (Hellsten et al, 2008;Barton et al, 2004;Zhang et al, 2010;Zhang et al, 2007;Xi et al, 2005;Sun et al, 2008;Gu et al, 2008;Turkson et al, 2004b;Turkson et al, 2005;Lee et al, 2006). Some of these inhibitors have been tested in animal models and they appear to cause regression of xenograft tumors.…”