Genome-wide siRNA screen for modulators of cell death induced by proteasome inhibitor bortezomib.
| Autor: | Chen S; Discovery Technologies, Discovery Oncology Biology, and Medical Biostatistics, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA., 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 |
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| Jazyk: | angličtina |
| Zdroj: | Cancer research [Cancer Res] 2010 Jun 01; Vol. 70 (11), pp. 4318-26. Date of Electronic Publication: 2010 May 11. |
| DOI: | 10.1158/0008-5472.CAN-09-4428 |
| Abstrakt: | 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. (Copyright 2010 AACR.) |
| Databáze: | MEDLINE |
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