Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity

Genes and Development - Tập 25 Số 20 - Trang 2125-2136 - 2011
Yuchen Chien1, Claudio Scuoppo2, Xiaowo Wang3, Xiaowei Fang4, Brian M. Balgley5, Jessica E. Bolden6, Prem K. Premsrirut6, Weijun Luo6, Agustin Chicas6, Cheng S. Lee4, Scott C. Kogan7,8, Scott W. Lowe9,6,10
1Cold Spring Harbor Laboratory, New York 11724, USA
2Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
3Ministry of Education (MOE) Key Laboratory of Bioinformatics, Bioinformatics Division, Tsinghua National Laboratory for Information Science and Technology (TNLIST), Department of Automation, Tsinghua University, Beijing 10084, China;
4Department of Chemistry and Biochemistry University of Maryland, College Park, Maryland 20742 USA
5Calibrant, Gaithersburg, Maryland 20878, USA;
6Cold Spring Harbor Laboratory Cold Spring Harbor, New York, 11724 USA
7Department of Laboratory Medicine
8Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143, USA
9Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
10Howard Hughes Medical Institute, Cold Spring Harbor, New York 11724, USA

Tóm tắt

Cellular senescence acts as a potent barrier to tumorigenesis and contributes to the anti-tumor activity of certain chemotherapeutic agents. Senescent cells undergo a stable cell cycle arrest controlled by RB and p53 and, in addition, display a senescence-associated secretory phenotype (SASP) involving the production of factors that reinforce the senescence arrest, alter the microenvironment, and trigger immune surveillance of the senescent cells. Through a proteomics analysis of senescent chromatin, we identified the nuclear factor-κB (NF-κB) subunit p65 as a major transcription factor that accumulates on chromatin of senescent cells. We found that NF-κB acts as a master regulator of the SASP, influencing the expression of more genes than RB and p53 combined. In cultured fibroblasts, NF-κB suppression causes escape from immune recognition by natural killer (NK) cells and cooperates with p53 inactivation to bypass senescence. In a mouse lymphoma model, NF-κB inhibition bypasses treatment-induced senescence, producing drug resistance, early relapse, and reduced survival. Our results demonstrate that NF-κB controls both cell-autonomous and non-cell-autonomous aspects of the senescence program and identify a tumor-suppressive function of NF-κB that contributes to the outcome of cancer therapy.

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Tài liệu tham khảo

10.1016/j.cell.2008.03.038

10.1038/sj.onc.1209942

10.1016/j.mad.2009.04.002

10.1093/emboj/cdg417

10.1016/j.cell.2005.02.003

10.1038/nrm2233

10.1038/nrc2696

10.1016/j.ccr.2010.01.023

10.1038/nature07968

10.1371/journal.pbio.0060301

10.1038/nature01283

10.1038/nature08638

10.1038/nature09535

2000, PML is induced by oncogenic ras and promotes premature senescence, Genes Dev, 14, 2015, 10.1101/gad.14.16.2015

10.1016/j.molmed.2010.03.003

10.1091/mbc.E04-05-0392

10.1038/sj.onc.1209943

10.1111/j.0105-2896.2006.00375.x

Jing H , Kase J , Dörr JR , Milanovic M , Lenze D , Grau M , Beuster G , Ji S , Reimann M , Lenz P , . 2011. Opposing roles of NF-κB in anti-cancer treatment outcome unveiled by cross-species investigations. Genes Dev (this issue). doi: 10.1101/gad.17620611.

10.1038/nature04870

10.1038/ncb1448

10.1016/j.cell.2008.06.049

10.1073/pnas.211053698

10.1038/nrc2560

10.1016/j.cell.2008.03.039

10.1101/gad.1971610

1997, p53-mediated cell cycle arrest and apoptosis, Leukemia, 11, 324

10.1101/gad.12.19.3008

10.1128/MCB.20.8.2915-2925.2000

10.1073/pnas.0809957105

10.1038/nature08462

10.1056/NEJMra062285

10.1016/S0092-8674(03)00401-X

10.1016/j.cell.2006.05.052

10.1200/JCO.2010.33.3252

10.1038/35059131

10.1038/35018127

10.1016/j.cell.2011.03.012

10.1038/ncb1909

2003, Tumor cell senescence in cancer treatment, Cancer Res, 63, 2705

10.1038/onc.2010.611

10.1038/ncb1314

10.1038/35009130

10.1038/nature00858

10.1101/gad.13.20.2670

10.1016/S0092-8674(02)00734-1

10.1016/S0092-8674(00)81902-9

10.1016/S0960-9822(99)80420-5

2002, DNA damage is able to induce senescence in tumor cells in vitro and in vivo, Cancer Res, 62, 1876

10.1016/j.cell.2007.12.032

10.1101/cshperspect.a000067

10.1038/embor.2009.197

1987, Long-term culture of murine bone marrow precursors of B lymphocytes, Methods Enzymol, 150, 275, 10.1016/0076-6879(87)50085-4

1997, Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1, Mol Cell Biol, 17, 5598, 10.1128/MCB.17.9.5598

10.1038/nature05529

10.1128/MCB.02019-06

10.1101/gad.12.19.2997

10.1101/gad.1199904

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Genes and Development

Tập 25 Số 20

2125-2136

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