Oncotarget

Research Papers:

A newly identified berberine derivative induces cancer cell senescence by stabilizing endogenous G-quadruplexes and sparking a DNA damage response at the telomere region

Yun-Xia Xiong _, Hua-Fei Su, Peng Lv, Yan Ma, Shi-Ke Wang, Hui Miao, Hui-Yun Liu, Jia-Heng Tan, Tian-Miao Ou, Lian-Quan Gu and Zhi-Shu Huang

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Oncotarget. 2015; 6:35625-35635. https://doi.org/10.18632/oncotarget.5521

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Abstract

Yun-Xia Xiong1, Hua-Fei Su1, Peng Lv1, Yan Ma2, Shi-Ke Wang1, Hui Miao1, Hui-Yun Liu1, Jia-Heng Tan1, Tian-Miao Ou1, Lian-Quan Gu1, Zhi-Shu Huang1

1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R.China

2Department of Medical Science, Shunde Polytechnic, Foshan 528333, P.R.China

Correspondence to:

Zhi-Shu Huang, e-mail: ceshzs@mail.sysu.edu.cn

Tian-Miao Ou, e-mail: outianm@mail.sysu.edu.cn

Keywords: berberine derivative, telomeric G-quadruplex, DNA damage, cancer cell senescence

Received: June 16, 2015     Accepted: September 28, 2015     Published: October 08, 2015

ABSTRACT

The guanine-rich sequences are able to fold into G-quadruplexes in living cells, making these structures promising anti-cancer drug targets. In the current study, we identified a small molecule, Ber8, from a series of 9-substituted berberine derivatives and found that it could induce acute cell growth arrest and senescence in cancer cells, but not in normal fibroblasts. Further analysis revealed that the cell growth arrest was directly associated with apparent cell cycle arrest, cell senescence, and profound DNA damage at the telomere region. Significantly, our studies also provided evidence that Ber8 could stabilize endogenous telomeric G-quadruplexes structures in cells. Ber8 could then induce the delocalization of TRF1 and POT1 from the telomere accompanied by a rapid telomere uncapping. These results provide compelling insights into direct binding of telomeric G-quadruplexes and might contribute to the development of more selective, effective anticancer drugs.


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