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Telomere‐based DNA damage responses: a new approach to melanoma
Author(s) -
Puri Neelu,
Eller Mark S.,
Byers H. Randolph,
Dykstra Sarah,
Kubera John,
Gilchrest Barbara A.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-1774com
Subject(s) - melanoma , dna damage , cancer research , telomere , apoptosis , oligonucleotide , biology , microbiology and biotechnology , cancer , cancer cell , dna , genetics
Melanoma is the most fatal skin cancer, often highly resistant to chemotherapy. Here we show that treatment with an 11‐base DNA oligonucleotide homologous to the telomere 3′ overhang sequence (T‐oligo) induces apoptosis of several established human melanoma cell lines, including the aggressive MM‐AN line, whereas normal human melanocytes exposed to the same or higher T‐oligo concentrations show only transient cell cycle arrest, implying that malignant cells are more sensitive to T‐oligo effects. When MM‐AN cells were briefly exposed to T‐oligo in culture and injected into the flank or tail vein of SCID mice, eventual tumor volume and number of metastases were reduced 85‐95% compared with control mice. Similarly, T‐oligos administered intralesionally or sys‐temically selectively inhibited the growth of previously established MM‐AN tumor nodules in the flank and peritoneal cavity by 85 to 90% without detectable toxicity. We previously showed that T‐oligos act through ATM, p95/Nbs1, E2F1, p16 INK4A , p53, and the p53 homologue p73 to modulate downstream effectors and now additionally demonstrate striking down‐regulation of the inhibitor of apoptosis protein livin/ML‐IAP. We suggest that T‐oligo mimics a physiologic DNA damage signal that is frequently masked in malignant cells and thereby activates innate cancer prevention responses. T‐oligos may provide a novel therapeutic approach to melanoma.—Puri, N., Eller, M. S., Byers, H. R., Dykstra, S., Kubera, J., Gilchrest, B. A. Te‐lomere‐based DNA damage responses: a new approach to melanoma.