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Published on: June 9, 2016
Telomere 3' overhang-specific DNA oligonucleotides induce autophagy in malignant glioma cells
Hiroshi Aoki1, Eiji Iwado, Mark S Eller
1Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Abstract:
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.
Insights
Telomere oligonucleotides (T-oligos) induce nonapoptotic cell death in malignant glioma cells by promoting autophagy. This novel therapeutic strategy shows promise for treating brain tumors, as T-oligos were effective in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Telomere 3' overhang-specific DNA oligonucleotides (T-oligos) are investigated as a potential cancer therapy.
- T-oligos are thought to induce cancer cell death by disrupting telomere loops.
Purpose of the Study:
- To investigate the antitumor mechanisms of T-oligos in human malignant glioma cells.
- To evaluate the efficacy of T-oligos in vitro and in vivo.
Main Methods:
- Cell proliferation assays
- Mitochondrial function analysis
- Autophagy marker assessment (microtubule-associated protein 1 light chain 3 conversion)
- Western blotting and protein microarray analysis to assess mTOR and STAT3 signaling
- In vivo survival studies in mice with intracranial glioma xenografts
Main Results:
- T-oligos inhibited malignant glioma cell proliferation via nonapoptotic cell death and mitochondrial hyperpolarization.
- Normal astrocytes exhibited resistance to T-oligos.
- T-oligo treatment induced autophagic features, including autophagic vacuoles and LC3-II conversion.
- T-oligos suppressed mTOR and STAT3 signaling pathways.
- T-oligos significantly prolonged survival in a mouse model of malignant glioma.
Conclusions:
- T-oligos induce nonapoptotic programmed cell death (autophagy) in malignant glioma cells.
- T-oligos demonstrate therapeutic potential for treating malignant glioma.
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