TY - JOUR
T1 - Aptamer to ErbB-2/HER2 enhances degradation of the target and inhibits tumorigenic growth
AU - Mahlknecht, Georg
AU - Maron, Ruth
AU - Mancini, Maicol
AU - Schechter, Bilha
AU - Sela, Michael
AU - Yarden, Yosef
N1 - National Cancer Institute [CA072981]; German-Israeli Project Cooperation; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; M.D. Moross Cancer Institute; Julius Baer Trust; Dukler Mudy Grant; Sergio Lombroso FoundationWe thank Beate Strehlitz (Helmholtz Centre for Environmental Research), Sara Lavi, and members of our teams for experimental guidance and advice. Our work is supported by National Cancer Institute Grant CA072981, the German-Israeli Project Cooperation, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the M.D. Moross Cancer Institute, the Julius Baer Trust, and a Dukler Mudy Grant. G. M. acknowledges the support of the Sergio Lombroso Foundation. Y.Y. is a Research Professor of the Israel Cancer Research fund, and the incumbent of the Harold and Zelda Goldenberg Professorial Chair. M. S. is the incumbent of the W. Garfield Weston Chair.
PY - 2013/5/14
Y1 - 2013/5/14
N2 - Aptamers, oligonucleotides able to avidly bind cellular targets, are emerging as promising therapeutic agents, analogous to monoclonal antibodies.We selected froma DNA library an aptamer specifically recognizing human epidermal growth factor receptor 2 (ErbB-2/HER2), a receptor tyrosine kinase, which is overexpressed in a variety of human cancers, including breast and gastric tumors. Treatment of human gastric cancer cells with a trimeric version (42 nucleotides) of the selected aptamer (14 nucleotides) resulted in reduced cell growth in vitro, but a monomeric version was ineffective. Likewise, when treated with the trimeric aptamer, animals bearing tumor xenografts of human gastric origin reflected reduced rates of tumor growth. The antitumor effect of the aptamer was nearly twofold stronger than that of a monoclonal anti-ErbB-2/HER2 antibody. Consistent with aptamer-induced intracellular degradation of ErbB-2/HER2, incubation of gastric cancer cells with the trimeric aptamer promoted translocation of ErbB-2/HER2 from the cell surface to cytoplasmic puncta. This translocation was associated with a lysosomal hydrolase-dependent clearance of the ErbB-2/HER2 protein from cell extracts. We conclude that targeting ErbB-2/HER2 with DNA aptamers might retard the tumorigenic growth of gastric cancer by means of accelerating lysosomal degradation of the oncoprotein. This work exemplifies the potential pharmacological utility of aptamers directed at cell surface proteins, and it highlights an endocytosis-mediated mechanism of tumor inhibition.
AB - Aptamers, oligonucleotides able to avidly bind cellular targets, are emerging as promising therapeutic agents, analogous to monoclonal antibodies.We selected froma DNA library an aptamer specifically recognizing human epidermal growth factor receptor 2 (ErbB-2/HER2), a receptor tyrosine kinase, which is overexpressed in a variety of human cancers, including breast and gastric tumors. Treatment of human gastric cancer cells with a trimeric version (42 nucleotides) of the selected aptamer (14 nucleotides) resulted in reduced cell growth in vitro, but a monomeric version was ineffective. Likewise, when treated with the trimeric aptamer, animals bearing tumor xenografts of human gastric origin reflected reduced rates of tumor growth. The antitumor effect of the aptamer was nearly twofold stronger than that of a monoclonal anti-ErbB-2/HER2 antibody. Consistent with aptamer-induced intracellular degradation of ErbB-2/HER2, incubation of gastric cancer cells with the trimeric aptamer promoted translocation of ErbB-2/HER2 from the cell surface to cytoplasmic puncta. This translocation was associated with a lysosomal hydrolase-dependent clearance of the ErbB-2/HER2 protein from cell extracts. We conclude that targeting ErbB-2/HER2 with DNA aptamers might retard the tumorigenic growth of gastric cancer by means of accelerating lysosomal degradation of the oncoprotein. This work exemplifies the potential pharmacological utility of aptamers directed at cell surface proteins, and it highlights an endocytosis-mediated mechanism of tumor inhibition.
UR - http://www.scopus.com/inward/record.url?scp=84877854501&partnerID=8YFLogxK
U2 - https://doi.org/10.1073/pnas.1302594110
DO - https://doi.org/10.1073/pnas.1302594110
M3 - مقالة
SN - 0027-8424
VL - 110
SP - 8170
EP - 8175
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -