Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction.
Direct experimental evidence implicates telomere erosion as a primary cause of cellular senescence. Using a well characterized model system for breast cancer, we define here the molecular and cellular consequences of adriamycin treatment in breast tumor cells. Cells acutely exposed to adriamycin exhibited an increase in p53 activity, a decline in telomerase activity, and a dramatic increase in beta-galactosidase, a marker of senescence. Inactivation of wild-type p53 resulted in a transition of the cellular response to adriamycin treatment from replicative senescence to delayed apoptosis, demonstrating that p53 plays an integral role in the fate of breast tumor cells treated with DNA-damaging agents. Stable introduction of hTERT, the catalytic protein component of telomerase, into MCF-7 cells caused an increase in telomerase activity and telomere length. Treatment of MCF-7-hTERT cells with adriamycin produced an identical senescence response as controls without signs of telomere shortening, indicating that the senescence after treatment is telomere length-independent. However, we found that exposure to adriamycin resulted in an overrepresentation of cytogenetic changes involving telomeres, showing an altered telomere state induced by adriamycin is probably a causal factor leading to the senescence phenotype. To our knowledge, these data are the first to demonstrate that the mechanism of adriamycin-induced senescence is dependent on both functional p53 and telomere dysfunction rather than overall shortening.
Elmore
Lynne W
LW
Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0662, USA.
Rehder
Catherine W
CW
Di
Xu
X
McChesney
Patricia A
PA
Jackson-Cook
Colleen K
CK
Gewirtz
David A
DA
Holt
Shawn E
SE
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016922:Cellular Senescence / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors; D016615:Telomere; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000903:Antibiotics, Antineoplastic; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D019098:Telomerase