Inhibition of melanoma growth and metastasis by ATF2-derived peptides
Inhibition of melanoma growth and metastasis by ATF2-derived peptides
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DOI：
10.1158/0008-5472.can-04-0714
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发表时间：
2004-11-15
期刊：
影响因子：
11.2
通讯作者：
Ronai, Z
中科院分区：
文献类型：
--
作者：
Bhoumik, A;Gangi, L;Ronai, Z
黑色素瘤对凋亡的抵抗以及其生长和转移能力，可以通过表达来源于ATF2的氨基酸(AA)51到100的多肽来克服。在这里，我们发现ATF2((51-100))在人黑色素瘤细胞中的表达减少了它们在裸鼠中的咆哮，这一点在蛋白激酶抑制剂UCN-01或SB203580治疗后被额外地抑制。将由HIV-TAT和ATF2的AS51~100组成的融合蛋白注射到西南黑色素瘤中，可有效地抑制其生长和转移，直至完全消退。此外，表达与ATF2的AS 51至60相对应的10aa多肽使黑色素瘤细胞对自发凋亡敏感，这与caspase 9和聚(ADP-核糖)聚合酶裂解的激活相一致，并抑制了它们在体内的生长。10aa多肽增加c-jun氨基末端激酶与c-jun的结合，但不增加与ATF2的结合，导致tre介导的转录增加。我们的研究指出了ATF2多肽活性的潜在机制，同时强调了它在药物设计中的可能用途。
The resistance of melanoma to apoptosis, as well as its growth am 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 growl 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 as 51 to 100 of ATF2 into SW melanomas efficiently inhibits their growth and their metastasis up to complete regression. Additionally, expression of a 10aa peptide that cor responds to as 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 NH2-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.