A G-quadruplex stabilizer induces M-phase cell cycle arrest

Yuan Chin Tsai, Haiyan Qi, Chao P. Lin, Ren K. Lin, John E. Kerrigan, Suzanne G. Rzuczek, Edmond J. LaVoie, Joseph E. Rice, Daniel S. Pilch, Yi Lisa Lyu, Leroy F. Liu

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41 引文 斯高帕斯(Scopus)

摘要

G-quadruplex stabilizers such as telomestatin and HXDV bind with exquisite specificity to G-quadruplexes, but not to triplex, duplex, or single-stranded DNAs. Studies have suggested that the antiproliferative and possibly anti-tumor activities of these compounds are linked to their inhibitory effect on telomerase and/or telomere function. In the current studies, we show that HXDV, a synthetic analog of telomestatin, exhibits antiproliferative activity against both telomerase-positive and -negative cells and induces robust apoptosis within 16 h of treatment, suggesting a mode of action independent of telomerase. HXDV was also shown to inhibit cell cycle progression causing M-phase cell cycle arrest, as evidenced by accumulation of cells with 4 N DNA content, increased mitotic index, separated centrosomes, elevated histone H3 phosphorylation at Ser-10 (an M-phase marker), and defective chromosome alignment and spindle fiber assembly (revealed by time-lapse microscopy). The M-phase arrest caused by HXDV paralleled with reduction in the expression level of the major M-phase checkpoint regulator Aurora A. All these cellular effects appear to depend on the G-quadruplex binding activity of HXDV as its non-G-quadruplex binding analog, TXTLeu, is completely devoid of all these effects. In the aggregate, our results suggest that HXDV, which exhibits anti-proliferative and apoptotic activities, is also a novel M-phase blocker, with a mode of action dependent on its G-quadruplex binding activity.
原文英語
頁(從 - 到)22535-22543
頁數9
期刊Journal of Biological Chemistry
284
發行號34
DOIs
出版狀態已發佈 - 八月 21 2009
對外發佈Yes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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