Telomere 3' overhang-specific DNA oligonucleotides induce autophagy in malignant glioma cells.
Telomere 3' overhang-specific DNA oligonucleotides (T-oligos) induce cell death in cancer cells, presumably by mimicking telomere loop disruption. Therefore, T-oligos are considered an exciting new therapeutic strategy. The purpose of this study was to elucidate how T-oligos exert antitumor effects on human malignant glioma cells in vitro and in vivo. We demonstrated that T-oligos inhibited the proliferation of malignant glioma cells through induction of nonapoptotic cell death and mitochondria hyperpolarization, whereas normal astrocytes were resistant to T-oligos. Tumor cells treated with T-oligos developed features compatible with autophagy, with development of autophagic vacuoles and conversion of an autophagy-related protein, microtubule-associated protein 1 light chain 3 from type I (cytoplasmic form) to type II (membrane form of autophagic vacuoles). A reverse-phase protein microarray analysis and Western blotting revealed that treatment with T-oligos inhibited the mammalian target of the rapamycin (mTOR) and the signal transducer and activator of transcription 3 (STAT3). Moreover, pretreatment with T-oligos significantly prolonged the survival time of mice inoculated intracranially with malignant glioma cells compared with that of untreated mice and those treated with control oligonucleotides (P=0.0065 and P=0.043, respectively). These results indicate that T-oligos stimulate the induction of nonapoptotic autophagic also known as type II programmed cell death and are thus promising in the treatment of malignant glioma.
Aoki
Hiroshi
H
Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Iwado
Eiji
E
Eller
Mark S
MS
Kondo
Yasuko
Y
Fujiwara
Keishi
K
Li
Guang-Zhi
GZ
Hess
Kenneth R
KR
Siwak
Doris R
DR
Sawaya
Raymond
R
Mills
Gordon B
GB
Gilchrest
Barbara A
BA
Kondo
Seiji
S
D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism; D001343:Autophagy; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002470:Cell Survival; D002478:Cells, Cultured; D004247:DNA / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D005910:Glioma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins; D008928:Mitochondria / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology*; D040081:Protein Array Analysis; D011494:Protein Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000378:metabolism
C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D009841:Oligonucleotides; D050796:STAT3 Transcription Factor; D004247:DNA; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D019098:Telomerase; D020123:Sirolimus