Roles of mTOR and STAT3 in autophagy induced by telomere 3' overhang-specific DNA oligonucleotides.
Telomere 3' overhang-specific DNA oligonucleotides (T-oligos) induce cancer cell death, presumably by mimicking telomere loop disruption and are, therefore, considered a promising new therapeutic strategy. We previously demonstrated that T-oligos inhibit the proliferation of malignant glioma cells in vitro and in vivo by inducing non-apoptotic autophagy. Using a reverse-phase protein microarray analysis and Western blotting, we revealed that T-oligos inhibit the mammalian target of rapamycin (mTOR) and the signal transducer and activator of transcription 3 (STAT3). Moreover, rapamycin (mTOR inhibitor) and AG490 (STAT3 inhibitor) sensitize malignant glioma cells to T-oligos by augmenting autophagy. Although mTOR is well known as a negative regulator of autophagy, the relationship between STAT3 and autophagy has never been demonstrated, to our knowledge. These findings suggest that, by exhibiting a novel mechanism of inducing autophagy through inhibition of mTOR and STAT3, T-oligos are a promising therapeutic agent for treating malignant gliomas. Here, we discuss evidence for T-oligos' effects on cell signaling pathways that may explain their ability to stimulate autophagy by inhibiting STAT3 as well as mTOR.
Yokoyama
Tomohisa
T
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Kondo
Yasuko
Y
Kondo
Seiji
S
D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000494:pharmacology*; D011494:Protein Kinases / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D020032:Tyrphostins / Q000494:pharmacology
D009838:Oligodeoxyribonucleotides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus