Novel single-stranded oligonucleotides that inhibit signal transducer and activator of transcription 3 induce apoptosis in vitro and in vivo in prostate cancer cell lines.
Signal transducers and activators of transcription (STAT) were originally discovered as components of cytokine signal transduction pathways. Persistent activation of one of these transcription factors, STAT3, is a feature of many malignancies, including hormone-resistant prostate cancer. In this regard, malignant cells expressing persistently activated STAT3 become dependent on it for survival, thus rendering STAT3 a potential molecular target for therapy of hormone-resistant prostate cancer. Previously, we reported that antisense oligonucleotides specific for STAT3 were better at inducing apoptosis than inhibitors of JAK1 or JAK2, the upstream activating kinases of STAT3. Here, we report that novel single-stranded oligonucleotides, which putatively block STAT3-DNA binding, were better at inducing hormone-resistant prostate cancer apoptosis than antisense STAT3 oligonucleotides. We observed that the novel STAT3-inhibiting oligonucleotides induced apoptosis by a mitochondrial-dependent pathway involving the activation of caspase-3. Prostate cell lines not expressing persistently activated STAT3 did not become apoptotic after treatment with these same oligonucleotides. Scrambled-sequence control oligonucleotides had none of the effects of the active sequence oligonucleotides on any variable measured. Furthermore, the novel STAT3-inhibiting oligonucleotides, but not scrambled-sequence control oligonucleotide, significantly reduced the volume of s.c. DU145 tumors in vivo. Histologic examination of the tumors revealed no infiltrate of mononuclear or granulocytic cells, which would be indicative of evocation of a nonspecific immune response by the oligonucleotides. We conclude that single-stranded oligonucleotides based on the binding sequences of STAT3 are an additional strategy to design inhibitors for this molecular target and that these inhibitors should be useful as experimental therapeutics for hormone-resistant prostate cancer.
Barton
Beverly E
BE
Division of Urology, Department of Surgery, University of Medicine and Dentistry-New Jersey Medical School, MSB G519, 185 South Orange Avenue, Newark, NJ 07103, USA. bartonbe@umdnj.edu
Murphy
Thomas F
TF
Shu
Ping
P
Huang
Hosea F
HF
Meyenhofer
Markus
M
Barton
Arnold
A
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D066298:In Vitro Techniques; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000473:pathology; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009841:Oligonucleotides / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000628:therapy*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D050796:STAT3 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics*; D014162:Transfection
D004268:DNA-Binding Proteins; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D004247:DNA; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2