Inhibition of melanoma growth and metastasis by ATF2-derived peptides.
The resistance of melanoma to apoptosis, as well as its growth and metastasis capabilities, can be overcome by expression of a peptide derived from amino acid (aa) 51 to 100 of ATF2. Here we show that expression of ATF2((51-100)) in human melanoma cells reduced their growth in nude mice, which was additionally inhibited upon treatment with protein kinase inhibitors UCN-01 or SB203580. Injection of a fusion protein consisting of HIV-TAT and aa 51 to 100 of ATF2 into SW1 melanomas efficiently inhibits their growth and their metastasis up to complete regression. Additionally, expression of a 10aa peptide that corresponds to aa 51 to 60 of ATF2 sensitizes melanoma cells to spontaneous apoptosis, which coincides with activation of caspase 9 and poly(ADP-ribose) polymerase cleavage, and inhibit their growth in vivo. The 10aa peptide increases the association of c-Jun NH(2)-terminal kinase with c-Jun but not with ATF2, resulting in concomitant increase in TRE-mediated transcription. Our study points to mechanisms underlying the activities of the ATF2 peptide while highlighting its possible use in drug design.
Bhoumik
Anindita
A
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA.
Gangi
Lisa
L
Ronai
Ze'ev
Z
D051698:Activating Transcription Factor 2; D000818:Animals; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry*; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000473:pathology*; D014157:Transcription Factors / Q000737:chemistry*
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D010455:Peptides; D014157:Transcription Factors