Antiproliferative activity of G-rich oligonucleotides correlates with protein binding.
Oligonucleotides have been extensively studied as antisense or antigene agents that can potentially modulate the expression of specific genes. These strategies rely on sequence-specific hybridization of the oligonucleotide to mRNA or genomic DNA. Recently, it has become clear that oligonucleotides often have biological activities that cannot be attributed to their sequence-specific interactions with nucleic acids. Here we describe a series of guanosine-rich phosphodiester oligodeoxynucleotides that strongly inhibit proliferation in a number of human tumor cell lines. The presence of G-quartets in the active oligonucleotides is demonstrated using an UV melting technique. We show that G-rich oligonucleotides bind to a specific cellular protein and that the biological activity of the oligonucleotides correlates with binding to this protein. The G-rich oligonucleotide-binding protein was detected in both nuclear and cytoplasmic extracts and in proteins derived from the plasma membrane of cells. We present strong evidence that this protein is nucleolin, a multifunctional phosphoprotein whose levels are related to the rate of cell proliferation. Our results indicate that binding of G-rich oligonucleotides to nucleolin may be responsible for their non-sequence-specific effects. Furthermore, these oligonucleotides represent a new class of potentially therapeutic agents with a novel mechanism of action.
Bates
P J
PJ
Department of Medicine, Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, Alabama 35294-3300, USA.
Kahlon
J B
JB
Thomas
S D
SD
Trent
J O
JO
Miller
D M
DM
D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects*; D017931:DNA Primers; D006147:Guanine / Q000737:chemistry*; D006801:Humans; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D009841:Oligonucleotides; D006147:Guanine