Genome-Wide siRNA Screen for Modulators of Cell Death Induced by Proteasome Inhibitor Bortezomib

被引：78

作者：

Chen, Siquan ^{[2
]}

Blank, Jonathan L. ^{[1
]}

Peters, Theodore ^{[2
]}

Liu, Xiaozhen J. ^{[1
]}

Rappoli, David M. ^{[2
]}

Pickard, Michael D. ^{[3
]}

Menon, Saurabh ^{[2
]}

Yu, Jie ^{[1
]}

Driscoll, Denise L. ^{[1
]}

Lingaraj, Trupti ^{[1
]}

Burkhardt, Anne L. ^{[1
]}

Chen, Wei ^{[1
]}

Garcia, Khristofer ^{[2
]}

Sappal, Darshan S. ^{[1
]}

Gray, Jesse ^{[2
]}

Hales, Paul ^{[2
]}

Leroy, Patrick J. ^{[1
]}

Ringeling, John ^{[2
]}

Rabino, Claudia ^{[1
]}

Spelman, James J. ^{[1
]}

Morgenstern, Jay P. ^{[2
]}

Lightcap, Eric S. ^{[1
]}

机构：

[1] Millennium Pharmaceut Inc, Discovery Oncol Biol, Cambridge, MA 02139 USA

[2] Millennium Pharmaceut Inc, Discovery Technol, Cambridge, MA 02139 USA

[3] Millennium Pharmaceut Inc, Med Biostat, Cambridge, MA 02139 USA

来源：

CANCER RESEARCH | 2010年 / 70卷 / 11期

关键词：

UNFOLDED PROTEIN RESPONSE; INITIATION-FACTOR; 5A; C-MYC; TRANSLATION; RESISTANCE; APOPTOSIS; SUPPRESSORS; DEPLETION; MELPHALAN; PATHWAY;

D O I：

10.1158/0008-5472.CAN-09-4428

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Multiple pathways have been proposed to explain how proteasome inhibition induces cell death, but mechanisms remain unclear. To approach this issue, we performed a genome-wide siRNA screen to evaluate the genetic determinants that confer sensitivity to bortezomib (Velcade (R); PS-341). This screen identified 100 genes whose knockdown affected lethality to bortezomib and to a structurally diverse set of other proteasome inhibitors. A comparison of three cell lines revealed that 39 of 100 genes were commonly linked to cell death. We causally linked bortezomib-induced cell death to the accumulation of ASF1B, Myc, ODC1, Noxa, BNIP3, Gadd45 alpha, p-SMC1A, SREBF1, and p53. Our results suggest that proteasome inhibition promotes cell death primarily by dysregulating Myc and polyamines, interfering with protein translation, and disrupting essential DNA damage repair pathways, leading to programmed cell death. Cancer Res; 70( 11); 4318-26. (C) 2010 AACR.

引用

页码：4318 / 4326

页数：9

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