Genome-wide siRNA screen for modulators of cell death induced by proteasome inhibitor bortezomib

Siquan Chen; Jonathan L Blank; Theodore Peters; Xiaozhen J Liu; David M Rappoli; Michael D Pickard; Saurabh Menon; Jie Yu; Denise L Driscoll; Trupti Lingaraj; Anne L Burkhardt; Wei Chen; Khristofer Garcia; Darshan S Sappal; Jesse Gray; Paul Hales; Patrick J Leroy; John Ringeling; Claudia Rabino; James J Spelman; Jay P Morgenstern; Eric S Lightcap

doi:10.1158/0008-5472.CAN-09-4428

Genome-wide siRNA screen for modulators of cell death induced by proteasome inhibitor bortezomib

Siquan Chen
, Jonathan L Blank
, Theodore Peters
, Xiaozhen J Liu
, David M Rappoli
, Michael D Pickard
, Saurabh Menon
, Jie Yu
, Denise L Driscoll
, Trupti Lingaraj
, Anne L Burkhardt
, Wei Chen
, Khristofer Garcia
, Darshan S Sappal
, Jesse Gray
, Paul Hales
, Patrick J Leroy
, John Ringeling
, Claudia Rabino
, James J Spelman

Jay P Morgenstern, Eric S Lightcap

Research output: Contribution to journal › Article › peer-review

Abstract

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, Gadd45alpha, 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.

Original language	English
Pages (from-to)	4318-26
Number of pages	9
Journal	Cancer Research
Volume	70
Issue number	11
DOIs	https://doi.org/10.1158/0008-5472.CAN-09-4428
Publication status	Published - 1 Jun 2010
Externally published	Yes

Keywords

Antineoplastic Agents/pharmacology
Boronic Acids/pharmacology
Bortezomib
Cell Death/drug effects
Colonic Neoplasms/drug therapy
DNA Damage
Gene Knockdown Techniques
HCT116 Cells
HeLa Cells
Humans
Intracellular Signaling Peptides and Proteins/genetics
Melanoma/drug therapy
Protease Inhibitors/pharmacology
Proteasome Inhibitors
Protein Serine-Threonine Kinases/biosynthesis
Proto-Oncogene Proteins c-myc/biosynthesis
Pyrazines/pharmacology
RNA, Small Interfering/genetics
Ribosomes/drug effects
TOR Serine-Threonine Kinases
Transfection

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10.1158/0008-5472.CAN-09-4428

Cite this

Chen, S., Blank, J. L., Peters, T., Liu, X. J., Rappoli, D. M., Pickard, M. D., Menon, S., Yu, J., Driscoll, D. L., Lingaraj, T., Burkhardt, A. L., Chen, W., Garcia, K., Sappal, D. S., Gray, J., Hales, P., Leroy, P. J., Ringeling, J., Rabino, C., ... Lightcap, E. S. (2010). Genome-wide siRNA screen for modulators of cell death induced by proteasome inhibitor bortezomib. Cancer Research, 70(11), 4318-26. https://doi.org/10.1158/0008-5472.CAN-09-4428

@article{22f4f5b4c1a64e4383e2c8795b120462,

title = "Genome-wide siRNA screen for modulators of cell death induced by proteasome inhibitor bortezomib",

abstract = "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, Gadd45alpha, 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.",

keywords = "Antineoplastic Agents/pharmacology, Boronic Acids/pharmacology, Bortezomib, Cell Death/drug effects, Colonic Neoplasms/drug therapy, DNA Damage, Gene Knockdown Techniques, HCT116 Cells, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins/genetics, Melanoma/drug therapy, Protease Inhibitors/pharmacology, Proteasome Inhibitors, Protein Serine-Threonine Kinases/biosynthesis, Proto-Oncogene Proteins c-myc/biosynthesis, Pyrazines/pharmacology, RNA, Small Interfering/genetics, Ribosomes/drug effects, TOR Serine-Threonine Kinases, Transfection",

author = "Siquan Chen and Blank, \{Jonathan L\} and Theodore Peters and Liu, \{Xiaozhen J\} and Rappoli, \{David M\} and Pickard, \{Michael D\} and Saurabh Menon and Jie Yu and Driscoll, \{Denise L\} and Trupti Lingaraj and Burkhardt, \{Anne L\} and Wei Chen and Khristofer Garcia and Sappal, \{Darshan S\} and Jesse Gray and Paul Hales and Leroy, \{Patrick J\} and John Ringeling and Claudia Rabino and Spelman, \{James J\} and Morgenstern, \{Jay P\} and Lightcap, \{Eric S\}",

year = "2010",

month = jun,

day = "1",

doi = "10.1158/0008-5472.CAN-09-4428",

language = "English",

volume = "70",

pages = "4318--26",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "11",

}

Chen, S, Blank, JL, Peters, T, Liu, XJ, Rappoli, DM, Pickard, MD, Menon, S, Yu, J, Driscoll, DL, Lingaraj, T, Burkhardt, AL, Chen, W, Garcia, K, Sappal, DS, Gray, J, Hales, P, Leroy, PJ, Ringeling, J, Rabino, C, Spelman, JJ, Morgenstern, JP & Lightcap, ES 2010, 'Genome-wide siRNA screen for modulators of cell death induced by proteasome inhibitor bortezomib', Cancer Research, vol. 70, no. 11, pp. 4318-26. https://doi.org/10.1158/0008-5472.CAN-09-4428

TY - JOUR

T1 - Genome-wide siRNA screen for modulators of cell death induced by proteasome inhibitor bortezomib

AU - Chen, Siquan

AU - Blank, Jonathan L

AU - Peters, Theodore

AU - Liu, Xiaozhen J

AU - Rappoli, David M

AU - Pickard, Michael D

AU - Menon, Saurabh

AU - Yu, Jie

AU - Driscoll, Denise L

AU - Lingaraj, Trupti

AU - Burkhardt, Anne L

AU - Chen, Wei

AU - Garcia, Khristofer

AU - Sappal, Darshan S

AU - Gray, Jesse

AU - Hales, Paul

AU - Leroy, Patrick J

AU - Ringeling, John

AU - Rabino, Claudia

AU - Spelman, James J

AU - Morgenstern, Jay P

AU - Lightcap, Eric S

PY - 2010/6/1

Y1 - 2010/6/1

N2 - 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, Gadd45alpha, 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.

AB - 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, Gadd45alpha, 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.

KW - Antineoplastic Agents/pharmacology

KW - Boronic Acids/pharmacology

KW - Bortezomib

KW - Cell Death/drug effects

KW - Colonic Neoplasms/drug therapy

KW - DNA Damage

KW - Gene Knockdown Techniques

KW - HCT116 Cells

KW - HeLa Cells

KW - Humans

KW - Intracellular Signaling Peptides and Proteins/genetics

KW - Melanoma/drug therapy

KW - Protease Inhibitors/pharmacology

KW - Proteasome Inhibitors

KW - Protein Serine-Threonine Kinases/biosynthesis

KW - Proto-Oncogene Proteins c-myc/biosynthesis

KW - Pyrazines/pharmacology

KW - RNA, Small Interfering/genetics

KW - Ribosomes/drug effects

KW - TOR Serine-Threonine Kinases

KW - Transfection

U2 - 10.1158/0008-5472.CAN-09-4428

DO - 10.1158/0008-5472.CAN-09-4428

M3 - Article

C2 - 20460535

SN - 0008-5472

VL - 70

SP - 4318

EP - 4326

JO - Cancer Research

JF - Cancer Research

IS - 11

ER -

Genome-wide siRNA screen for modulators of cell death induced by proteasome inhibitor bortezomib

Abstract

Keywords

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