Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway

被引：17

作者：

Ando, Koji ^{[1
]}

Shah, Ankur K. ^{[1
]}

Sachdev, Vibhu ^{[1
]}

Kleinstiver, Benjamin P. ^{[2
,3
]}

Taylor-Parker, Julian ^{[1
]}

Welch, Moira M. ^{[2
]}

Hu, Yiheng ^{[4
]}

Salgia, Ravi ^{[5
]}

White, Forest M. ^{[6
]}

Parvin, Jeffrey D. ^{[4
]}

Ozonoff, Al ^{[7
]}

Rameh, Lucia E. ^{[8
]}

Joung, J. Keith ^{[2
,3
]}

Bharti, Ajit K. ^{[1
]}

机构：

[1] Boston Univ, Sch Med, Dept Med, Div Hematol Oncol, Boston, MA 02118 USA

[2] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA

[3] Harvard Med Sch, Dept Pathol, Boston, MA USA

[4] Ohio State Univ, Ctr Comprehens Canc, Dept Biomed Informat, Columbus, OH 43210 USA

[5] City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA USA

[6] MIT, Koch Inst Integrat Canc Res, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[7] Boston Childrens Hosp, Ctr Patient Safety & Qual Res, Boston, MA USA

[8] Boston Univ, Sch Med, Dept Med, Obes Res Ctr, Boston, MA 02118 USA

来源：

ONCOTARGET | 2017年 / 8卷 / 27期

基金：

加拿大自然科学与工程研究理事会; 美国国家卫生研究院;

关键词：

topoisomerase I; BRCA1; DNAPK; PTEN; ubiquitin proteasome pathway; DEPENDENT PROTEIN-KINASE; DOUBLE-STRAND BREAKS; DNA-DAMAGE; DRUG CAMPTOTHECIN; CATALYTIC SUBUNIT; MAMMALIAN-CELLS; LUNG-CANCER; E3; LIGASE; REPAIR; PHOSPHORYLATION;

D O I：

10.18632/oncotarget.16376

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Proteasomal degradation of topoisomerase I (topoI) is one of the most remarkable cellular phenomena observed in response to camptothecin (CPT). Importantly, the rate of topoI degradation is linked to CPT resistance. Formation of the topoI-DNA-CPT cleavable complex inhibits DNA re-ligation resulting in DNA-double strand break (DSB). The degradation of topoI marks the first step in the ubiquitin proteasome pathway (UPP) dependent DNA damage response (DDR). Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. A higher basal level of topoI-pS10 ensures rapid topoI degradation leading to CPT resistance. Importantly, PTEN regulates DNA-PKcs kinase activity in this pathway and PTEN deletion ensures DNA-PKcs dependent higher topoI-pS10, rapid topoI degradation and CPT resistance.

引用

页码：43733 / 43751

页数：19

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