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

被引：448

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

共 38 条

[1] THE C-MYC ONCOGENE DRIVEN BY IMMUNOGLOBULIN ENHANCERS INDUCES LYMPHOID MALIGNANCY IN TRANSGENIC MICE
ADAMS, JM
HARRIS, AW
PINKERT, CA
CORCORAN, LM
ALEXANDER, WS
CORY, S
PALMITER, RD
BRINSTER, RL
[J]. NATURE, 1985, 318 (6046) : 533 - 538
[2] c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription
Arabi, A
Wu, SQ
Ridderstråle, K
Bierhoff, H
Shiue, C
Fatyol, K
Fahlén, S
Hydbring, P
Söderberg, O
Grummt, I
Larsson, LG
Wright, APH
[J]. NATURE CELL BIOLOGY, 2005, 7 (03) : 303 - 310
[3] Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency
Barna, Maria
Pusic, Aya
Zollo, Ornella
Costa, Maria
Kondrashov, Nadya
Rego, Eduardo
Rao, Pulivarthi H.
Ruggero, Davide
[J]. NATURE, 2008, 456 (7224) : 971 - U79
[4] The multifunctional nucleolus
Boisvert, Francois-Michel
van Koningsbruggen, Silvana
Navascues, Joaquin
Lamond, Angus I.
[J]. NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2007, 8 (07) : 574 - 585
[5] The Nucleolus under Stress
Boulon, Severine
Westman, Belinda J.
Hutten, Saskia
Boisvert, Francois-Michel
Lamond, Angus I.
[J]. MOLECULAR CELL, 2010, 40 (02) : 216 - 227
[6] AKT Promotes rRNA Synthesis and Cooperates with c-MYC to Stimulate Ribosome Biogenesis in Cancer
Chan, Joanna C.
Hannan, Katherine M.
Riddell, Kim
Pui Yee Ng
Peck, Abigail
Lee, Rachel S.
Hung, Sandy
Astle, Megan V.
Bywater, Megan
Wall, Meaghan
Poortinga, Gretchen
Jastrzebski, Katarzyna
Sheppard, Karen E.
Hemmings, Brian A.
Hall, Michael N.
Johnstone, Ricky W.
McArthur, Grant A.
Hannan, Ross D.
Pearson, Richard B.
[J]. SCIENCE SIGNALING, 2011, 4 (188)
[7] Crosstalk Between c-Myc and Ribosome in Ribosomal Biogenesis and Cancer
Dai, Mu-Shui
Lu, Hua
[J]. JOURNAL OF CELLULAR BIOCHEMISTRY, 2008, 105 (03) : 670 - 677
[8] The c-Myc target gene network
Dang, Chi V.
O'Donnell, Kathryn A.
Zeller, Karen I.
Nguyen, Tam
Osthus, Rebecca C.
Li, Feng
[J]. SEMINARS IN CANCER BIOLOGY, 2006, 16 (04) : 253 - 264
[9] Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway
Deisenroth, C.
Zhang, Y.
[J]. ONCOGENE, 2010, 29 (30) : 4253 - 4260
[10] What the nucleolus says to a tumour pathologist
Derenzini, Massimo
Montanaro, Lorenzo
Trere, Davide
[J]. HISTOPATHOLOGY, 2009, 54 (06) : 753 - 762

← 1 2 3 4 →