Antisense telomerase treatment: Induction of two distinct pathways, apoptosis and differentiation

Seiji Kondo, Yoshikazu Tanaka, Yasuko Kondo, Masahiro Hitomi, Gene H. Barnett, Yukihito Ishizaka, Jinbo Liu, Talat Haqqi, Akiko Nishiyama, Bryant Villeponteau, John Kenneth Cowell, Barbara P. Barna

Research output: Contribution to journalArticle

179 Citations (Scopus)

Abstract

Telomerase, the enzyme that elongates telomeric DNA (ITAGGG)(n), may be involved in cellular immortality and oncogenesis. To investigate the effect of inhibition of telomerase on tumor cells, we transfected the antisense vector against the human telomerase RNA into human malignant glioma cells exhibiting telomerase activity. After 30 doublings, some subpopulations of transfectants expressed a high level of interleukin-1β-converting enzyme (ICE) protein and underwent apoptosis. In contrast, other subpopulations also showed enhanced ICE protein but escaped from apoptotic crisis and continued to grow, although their DNA synthesis, invasive ability, and tumorigenicity in nude mice were significantly reduced. Surviving cells demonstrated increased expression of glial fibrillary acidic protein and decreased motility, consistent with a more differentiated state. These cells also contained enhanced expression of the cyclin-dependent kinase inhibitors (CDKIs) p21 and p27. Treatment of surviving nonapoptotic cells with antisense oligonucleotides against p27, but not p21, induced apoptotic cell death, suggesting that p27 may have protected differentiating glioma cells from apoptosis. These data show that treatment with antisense telomerase inhibits telomerase activity and subsequently induces either apoptosis or differentiation. Regulation of these two distinct pathways may be dependent on the expression of ICE or CDKIs.

Original languageEnglish (US)
Pages (from-to)801-811
Number of pages11
JournalFASEB Journal
Volume12
Issue number10
StatePublished - Jul 8 1998
Externally publishedYes

Fingerprint

Telomerase
Caspase 1
Apoptosis
Glioma
Cells
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases
Antisense Oligonucleotides
Glial Fibrillary Acidic Protein
DNA
Cell death
Tumors
Proteins
Nude Mice
Carcinogenesis
Cell Death
Enzymes
Neoplasms

Keywords

  • CDKI
  • ICE
  • Oglionucleotide
  • p27
  • Tumor cells
  • Tumorigenicity

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Kondo, S., Tanaka, Y., Kondo, Y., Hitomi, M., Barnett, G. H., Ishizaka, Y., ... Barna, B. P. (1998). Antisense telomerase treatment: Induction of two distinct pathways, apoptosis and differentiation. FASEB Journal, 12(10), 801-811.

Antisense telomerase treatment : Induction of two distinct pathways, apoptosis and differentiation. / Kondo, Seiji; Tanaka, Yoshikazu; Kondo, Yasuko; Hitomi, Masahiro; Barnett, Gene H.; Ishizaka, Yukihito; Liu, Jinbo; Haqqi, Talat; Nishiyama, Akiko; Villeponteau, Bryant; Cowell, John Kenneth; Barna, Barbara P.

In: FASEB Journal, Vol. 12, No. 10, 08.07.1998, p. 801-811.

Research output: Contribution to journalArticle

Kondo, S, Tanaka, Y, Kondo, Y, Hitomi, M, Barnett, GH, Ishizaka, Y, Liu, J, Haqqi, T, Nishiyama, A, Villeponteau, B, Cowell, JK & Barna, BP 1998, 'Antisense telomerase treatment: Induction of two distinct pathways, apoptosis and differentiation', FASEB Journal, vol. 12, no. 10, pp. 801-811.
Kondo S, Tanaka Y, Kondo Y, Hitomi M, Barnett GH, Ishizaka Y et al. Antisense telomerase treatment: Induction of two distinct pathways, apoptosis and differentiation. FASEB Journal. 1998 Jul 8;12(10):801-811.
Kondo, Seiji ; Tanaka, Yoshikazu ; Kondo, Yasuko ; Hitomi, Masahiro ; Barnett, Gene H. ; Ishizaka, Yukihito ; Liu, Jinbo ; Haqqi, Talat ; Nishiyama, Akiko ; Villeponteau, Bryant ; Cowell, John Kenneth ; Barna, Barbara P. / Antisense telomerase treatment : Induction of two distinct pathways, apoptosis and differentiation. In: FASEB Journal. 1998 ; Vol. 12, No. 10. pp. 801-811.
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abstract = "Telomerase, the enzyme that elongates telomeric DNA (ITAGGG)(n), may be involved in cellular immortality and oncogenesis. To investigate the effect of inhibition of telomerase on tumor cells, we transfected the antisense vector against the human telomerase RNA into human malignant glioma cells exhibiting telomerase activity. After 30 doublings, some subpopulations of transfectants expressed a high level of interleukin-1β-converting enzyme (ICE) protein and underwent apoptosis. In contrast, other subpopulations also showed enhanced ICE protein but escaped from apoptotic crisis and continued to grow, although their DNA synthesis, invasive ability, and tumorigenicity in nude mice were significantly reduced. Surviving cells demonstrated increased expression of glial fibrillary acidic protein and decreased motility, consistent with a more differentiated state. These cells also contained enhanced expression of the cyclin-dependent kinase inhibitors (CDKIs) p21 and p27. Treatment of surviving nonapoptotic cells with antisense oligonucleotides against p27, but not p21, induced apoptotic cell death, suggesting that p27 may have protected differentiating glioma cells from apoptosis. These data show that treatment with antisense telomerase inhibits telomerase activity and subsequently induces either apoptosis or differentiation. Regulation of these two distinct pathways may be dependent on the expression of ICE or CDKIs.",
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