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Inhibition of melanoma growth and metastasis by ATF2-derived peptides
Anindita Bhoumik1, Lisa Gangi, Ze'ev Ronai
1Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA.
Abstract:
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.
Insights
A novel peptide derived from activating transcription factor 2 (ATF2) effectively inhibits melanoma growth and metastasis. This ATF2 peptide shows promise for developing new melanoma treatments by overcoming drug resistance and promoting apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Melanoma exhibits resistance to apoptosis, and possesses significant growth and metastasis capabilities.
- Activating transcription factor 2 (ATF2) plays a role in cellular processes relevant to cancer progression.
Purpose of the Study:
- To investigate the therapeutic potential of a peptide derived from amino acids 51-100 of ATF2 (ATF2(51-100)) in overcoming melanoma resistance.
- To elucidate the mechanisms by which ATF2 peptides inhibit melanoma growth and metastasis.
Main Methods:
- Expression of ATF2(51-100) in human melanoma cells and assessment of tumor growth in nude mice.
- Treatment of melanoma cells with protein kinase inhibitors (UCN-01, SB203580).
- In vivo studies using a fusion protein of HIV-TAT and ATF2(51-100) in SW1 melanomas.
- Analysis of a 10-amino acid peptide (aa 51-60) for apoptosis sensitization, caspase activation, and in vivo growth inhibition.
- Investigation of c-Jun NH(2)-terminal kinase (JNK) association with c-Jun and ATF2, and TRE-mediated transcription.
Main Results:
- Expression of ATF2(51-100) reduced melanoma growth in vivo, with further inhibition by UCN-01 or SB203580.
- A TAT-ATF2(51-100) fusion protein significantly inhibited melanoma growth, metastasis, and induced complete tumor regression.
- A 10aa ATF2 peptide sensitized melanoma cells to apoptosis, activating caspase 9 and PARP cleavage, and inhibited in vivo growth.
- The 10aa peptide increased JNK association with c-Jun, leading to enhanced TRE-mediated transcription.
Conclusions:
- The ATF2(51-100) peptide and its shorter derivative demonstrate significant potential for inhibiting melanoma progression.
- These ATF2-derived peptides offer a promising strategy for melanoma drug design by targeting key pathways involved in apoptosis and transcription.
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