RNA aptamers interfering with nucleophosmin oligomerization induce apoptosis of cancer cells.
Nucleophosmin (NPM) is a multifunctional protein involved in both proliferation and apoptosis. Importantly, NPM negatively regulates p53 and is frequently overexpressed in a wide variety of cancers. To identify inhibitory molecules of NPM, we used an in vitro selection method termed systematic evolution of ligands by exponential enrichment (SELEX) to select RNA aptamers that bind to NPM with high affinity and specificity. The selected RNA aptamers bind to the central acidic region of NPM and affect its oligomerization both in vitro and in vivo. Remarkably, expression of NPM-specific aptamers causes mislocalization of NPM in the nucleoplasm rather than in the nucleolus, suggesting that NPM oligomerization is important for its proper localization. Moreover, p14ARF is mislocalized in the nucleoplasm and p53 is upregulated in cells expressing NPM aptamers. In addition, cancer cells expressing NPM aptamers not only undergo apoptosis on their own, but are more susceptible to apoptosis induced by DNA-damaging agents as well. These results suggest that interfering with NPM oligomerization can inhibit NPM function and aptamers targeting NPM can serve as potential lead for developing anticancer drugs.
Jian
Y
Y
Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
Gao
Z
Z
Sun
J
J
Shen
Q
Q
Feng
F
F
Jing
Y
Y
Yang
C
C
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D052157:Aptamers, Nucleotide / Q000096:biosynthesis* / Q000235:genetics; D002466:Cell Nucleolus / Q000378:metabolism*; D049109:Cell Proliferation; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000090243:Nucleophosmin; D052156:SELEX Aptamer Technique; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D052157:Aptamers, Nucleotide; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; C495901:TP53 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin