On the significance of telomerase activity in human malignant glioma cells.
Telomerase is critical for tumor cell immortalization and is a novel target for cancer chemotherapy. Here, we examined whether telomerase is expressed in glioma cell lines, whether telomerase activity is regulated by bcl-2 or p53, and whether telomerase activity predicts response to chemotherapy. Further, we characterized the effects of a candidate telomerase inhibitor, penclomedine, in glioma cells. All 12 human malignant glioma cell lines examined were telomerase positive. Telomerase activity was not modulated during cell cycle progression, did not correlate with p53 status or bcl-2 family protein expression, and did not predict drug sensitivity, except for an association with resistance to carmustine. Ectopic bcl-2 expression did not enhance telomerase activity. Wild-type p53 reduced telomerase activity in cell lines retaining p53 activity but not in p53-mutant cell lines. Penclomedine killed glioma cells via an apoptotic, but death receptor-, bcl-2- and caspase-independent pathway, but did not inhibit telomerase and did not act synergistically with cytotoxic drugs. We conclude that telomerase activity does not account for the differential chemosensitivity of human glioma cells and that penclomedine kills glioma cells via a telomerase-independent pathway.
Vietor
M
M
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, School of Medicine, Hoppe-Seyler-Strasse 3, D-72076, Tübingen, Germany.
Winter
S
S
Groscurth
P
P
Naumann
U
U
Weller
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D022761:Gene Transfer, Horizontal / Q000187:drug effects / Q000502:physiology; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D010847:Picolines / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D019098:Telomerase / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D010847:Picolines; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C058388:penclomedine; D019098:Telomerase