Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network.
Oncogene-induced cellular senescence (OIS) is emerging as a potent cancer-protective response to oncogenic events, serving to eliminate early neoplastic cells from the proliferative pool. Using combined genetic and bioinformatic analysis, we find that OIS is linked specifically to the activation of an inflammatory transcriptome. Induced genes included the pleiotropic cytokine interleukin-6 (IL-6), which upon secretion by senescent cells acted mitogenically in a paracrine fashion. Unexpectedly, IL-6 was also required for the execution of OIS, but in a cell-autonomous mode. Its depletion caused the inflammatory network to collapse and abolished senescence entry and maintenance. Furthermore, we demonstrate that the transcription factor C/EBPbeta cooperates with IL-6 to amplify the activation of the inflammatory network, including IL-8. In human colon adenomas, IL-8 specifically colocalized with arrested, p16(INK4A)-positive epithelium. We propose a model in which the context-dependent cytostatic and promitogenic functions of specific interleukins contribute to connect senescence with an inflammatory phenotype and cancer.
Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Thomas
T
Kuilman
Chrysiis
C
Michaloglou
Liesbeth C W
LC
Vredeveld
Sirith
S
Douma
Remco
R
van Doorn
Christophe J
CJ
Desmet
Lucien A
LA
Aarden
Wolter J
WJ
Mooi
Daniel S
DS
Peeper
D000236:Adenoma / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence; D003110:Colonic Neoplasms / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D020869:Gene Expression Profiling; D006570:Heterochromatin; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D034622:RNA Interference; D015854:Up-Regulation
D022782:CCAAT-Enhancer-Binding Protein-beta; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006570:Heterochromatin; D015850:Interleukin-6; D016209:Interleukin-8