The role of telomeres in Etoposide induced tumor cell death.
Etoposide, a topoisomerase II poison is used in the treatment of a number of solid tumors. Contradictory data exist on the role of the telomere/telomerase complex in etoposide induced apoptosis. Therefore we examined the effects of etoposide treatment in the neuroblastoma cell line SHSY5Y, with very short telomeres and the acute lymphoblastic T cell line 1301, which displays extremely long telomeres. Both short-term and continuous exposure to the drug were examined. Etoposide induced widespread DNA damage followed by DNA damage foci formation and ultimately growth arrest and apoptosis in a concentration-dependent manner. However, length of telomeres and of single stranded telomeric G rich overhangs did not change significantly under the treatments in any cell line. There was no significant induction of single-strand breaks in the G-rich strand of telomeres. Telomerase activity was transiently upregulated under low concentrations of etoposide, while high concentrations resulted in decreased telomerase activity only after onset of apoptosis. Telomerase overexpression protected against etoposide induced apoptosis in fibroblasts. The data suggest that telomeres are not major signal transducers towards growth arrest or apoptosis after etoposide treatment. However, upregulation of telomerase might be part of an attempted adaptative response, which protects cells by a mechanism that might be independent of telomere length maintenance.
Jeyapalan
Jessie
J
Henry Wellcome Biogerontology Laboratory, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
Leake
Alan
A
Ahmed
Shaheda
S
Saretzki
Gabriele
G
Tilby
Michael
M
von Zglinicki
Thomas
T
D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D004247:DNA / Q000187:drug effects / Q000502:physiology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology*; D018816:Genes, cdc / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000187:drug effects* / Q000378:metabolism; D016615:Telomere / Q000187:drug effects* / Q000378:metabolism; D059005:Topoisomerase II Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004247:DNA; D019098:Telomerase; D004250:DNA Topoisomerases, Type II