Inhibition of tumor growth and metastasis of human melanoma by intracellular anti-ATF-1 single chain Fv fragment.
Activating transcription factor-1 (ATF-1) and cAMP-responsive element (CRE)-binding protein (CREB) have been implicated in cAMP and Ca2+-induced transcriptional activation. The expression of the transcription factors CREB and ATF-1 is upregulated in metastatic melanoma cells. However, how overexpression of ATF-1/CREB contributes to the acquisition of the metastatic phenotype remains unclear. Here, the effect of disrupting ATF-1 activity was investigated using intracellular expression of an inhibitory anti-ATF-1 single chain antibody fragment (ScFv). Intracellular expression of ScFv anti-ATF-1 in MeWo melanoma cells caused significant reduction in CRE-dependent promoter activation. In addition, expression of ScFv anti-ATF-1 in melanoma cells suppressed their tumorigenicity and metastatic potential in nude mice. ScFv anti-ATF-1 rendered the melanoma cells susceptible to thapsigargin-induced apoptosis in vitro and caused massive apoptosis in tumors transplanted subcutaneously into nude mice, suggesting that ATF-1 and its associated proteins act as survival factor for human melanoma cells. This is the first report to demonstrate the potential of ScFv anti-ATF-1 as an inhibitor of tumor growth and metastasis of solid tumor in vivo. Oncogene (2000).
Jean
D
D
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, TX 77030, USA.
Tellez
C
C
Huang
S
S
Davis
D W
DW
Bruns
C J
CJ
McConkey
D J
DJ
Hinrichs
S H
SH
Bar-Eli
M
M
D051697:Activating Transcription Factor 1; D000818:Animals; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics* / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008545:Melanoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D051697:Activating Transcription Factor 1; C497100:Atf1 protein, mouse; D004268:DNA-Binding Proteins; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D011994:Recombinant Proteins; D014157:Transcription Factors; C055966:immunoglobulin Fv