Telomere 3′ overhang-specific DNA oligonucleotides induce autophagy in malignant glioma cells

Hiroshi Aoki, Eiji Iwado, Mark S. Eller, Yasuko Kondo, Keishi Fujiwara, Guang Zhi Li, Kenneth R. Hess, Doris R. Siwak, Raymond Sawaya, Gordon B. Mills, Barbara A. Gilchrest, Seiji Kondo

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

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 reversephase 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.

Original languageEnglish (US)
Pages (from-to)2918-2930
Number of pages13
JournalFASEB Journal
Volume21
Issue number11
DOIs
StatePublished - Sep 2007
Externally publishedYes

Keywords

  • T-oligos
  • mTOR

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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