Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53

被引：460

作者：

Bywater, Megan J. ^{[1
,3
]}

Poortinga, Gretchen ^{[1
,6
]}

Sanij, Elaine ^{[1
,4
]}

Hein, Nadine ^{[1
]}

Peck, Abigail ^{[1
]}

Cullinane, Carleen ^{[1
]}

Wall, Meaghan ^{[7
]}

Cluse, Leonie ^{[1
]}

Drygin, Denis ^{[8
]}

Anderes, Kenna ^{[8
]}

Huser, Nanni ^{[8
]}

Proffitt, Chris ^{[8
]}

Bliesath, Joshua ^{[8
]}

Haddach, Mustapha ^{[8
]}

Schwaebe, Michael K. ^{[8
]}

Ryckman, David M. ^{[8
]}

Rice, William G. ^{[8
]}

Schmitt, Clemens ^{[9
,10
]}

Lowe, Scott W. ^{[13
]}

Johnstone, Ricky W. ^{[1
,4
]}

Pearson, Richard B. ^{[1
,5
,11
]}

McArthur, Grant A. ^{[1
,2
,6
]}

Hannan, Ross D. ^{[1
,2
,3
,5
,11
,12
]}

机构：

[1] Peter MacCallum Canc Ctr, Div Canc Res, Melbourne, Vic 3002, Australia

[2] Peter MacCallum Canc Ctr, Div Canc Med, Melbourne, Vic 3002, Australia

[3] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3010, Australia

[4] Univ Melbourne, Dept Pathol, Parkville, Vic 3010, Australia

[5] Univ Melbourne, Dept Biochem & Mol Biol, Parkville, Vic 3010, Australia

[6] Univ Melbourne, St Vincents Hosp, Dept Med, Fitzroy, Vic 3065, Australia

[7] St Vincents Hosp, Victorian Canc Cytogenet Serv, Fitzroy, Vic 3065, Australia

[8] Cylene Pharmaceut, San Diego, CA 92121 USA

[9] Charite, Mol Krebsforschungszentrum MKFZ, D-13353 Berlin, Germany

[10] Max Delbruck Ctr Mol Med, Berlin, Germany

[11] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia

[12] Univ Queensland, Sch Biomed Sci, St Lucia, Qld 4072, Australia

[13] Cold Spring Harbor Lab, Howard Hughes Med Inst, Cold Spring Harbor, NY 11724 USA

来源：

CANCER CELL | 2012年 / 22卷 / 01期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

RIBOSOMAL-PROTEIN L11; C-MYC; GRANULOCYTE DIFFERENTIATION; NUCLEOLAR DISRUPTION; DEPENDENT REGULATION; CELL-GROWTH; TRANSCRIPTION; BIOGENESIS; PATHWAY; UBF;

D O I：

10.1016/j.ccr.2012.05.019

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Increased transcription of ribosomal RNA genes (rDNA) by RNA Polymerase I is a common feature of human cancer, but whether it is required for the malignant phenotype remains unclear. We show that rDNA transcription can be therapeutically targeted with the small molecule CX-5461 to selectively kill B-lymphoma cells in vivo while maintaining a viable wild-type B cell population. The therapeutic effect is a consequence of nucleolar disruption and activation of p53-dependent apoptotic signaling. Human leukemia and lymphoma cell lines also show high sensitivity to inhibition of rDNA transcription that is dependent on p53 mutational status. These results identify selective inhibition of rDNA transcription as a therapeutic strategy for the cancer specific activation of p53 and treatment of hematologic malignancies.

引用

页码：51 / 65

页数：15

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