Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing, China.
PLoS One. 2013 Apr 26;8(4):e62348. doi: 10.1371/journal.pone.0062348. Print 2013.
G-quadruplexes (G4s) are four-stranded nucleic acid structures adopted by some repetitive guanine-rich sequences. Putative G-quadruplex-forming sequences (PQSs) are highly prevalent in human genome. Recently some G4s have been reported to have cancer-selective antiproliferative activity. A G4 DNA, AS1411, is currently in phase II clinical trials as an anticancer agent, which is reported to bind tumor cells by targeting surface nucleolin. AS1411 also has been extensively investigated as a target-recognition element for cancer cell specific drug delivery or cancer cell imaging. Here we show that, in addition to AS1411, intramolecular G4s with parallel structure (including PQSs in genes) have general binding activity to many cell lines with different affinity. The binding of these G4s compete with each other, and their targets are certain cellular surface proteins. The tested G4s exhibit enhanced cellular uptake than non-G4 sequences. This uptake may be through the endosome/lysosome pathway, but it is independent of cellular binding of the G4s. The tested G4s also show selective antiproliferative activity that is independent of their cellular binding. Our findings provide new insight into the molecular recognition of G4s by cells; offer new clues for understanding the functions of G4s in vivo, and may extend the potential applications of G4s.
四链体（G4s）是某些富含鸟嘌呤的重复序列采用的四种链核酸结构。假定的四链体形成序列（PQSs）在人类基因组中高度普遍。最近，一些 G4s 被报道具有癌症选择性抗增殖活性。一种 G4 DNA，AS1411，目前正在进行 II 期临床试验作为一种抗癌剂，据报道通过靶向表面核仁素与肿瘤细胞结合。AS1411 也被广泛研究作为用于癌症细胞特异性药物递送或癌症细胞成像的靶识别元件。在这里，我们表明，除了 AS1411 之外，具有平行结构的分子内 G4s（包括基因中的 PQSs）与具有不同亲和力的许多细胞系具有一般的结合活性。这些 G4s 的结合相互竞争，其靶标是某些细胞表面蛋白。测试的 G4s 比非 G4 序列表现出增强的细胞摄取。这种摄取可能是通过内体/溶酶体途径，但它独立于 G4s 的细胞结合。测试的 G4s 还表现出独立于其细胞结合的选择性抗增殖活性。我们的发现为细胞对 G4s 的分子识别提供了新的见解；为理解体内 G4s 的功能提供了新的线索，并可能扩展 G4s 的潜在应用。
