Quantifying pharmacologic suppression of cellular senescence: prevention of cellular hypertrophy versus preservation of proliferative potential

被引:77
作者
Demidenko, Zoya N.
Blagosklonny, Mikhail V. [1 ]
机构
[1] Roswell Pk Canc Inst, Dept Cell Stress Biol, BLSC, Buffalo, NY 14263 USA
来源
AGING-US | 2009年 / 1卷 / 12期
关键词
cellular senescence; cellular hypertrophy; aging-suppression; rapamycin; mTOR; CELLS; ARREST; INHIBITION; SECRETION; RAPAMYCIN; PROTEIN; CANCER; LEADS;
D O I
10.18632/aging.100115
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Development of agents that suppress aging (aging suppressants) requires quantification of cellular senescence. Cellular senescence in vitro is characterized by a large cell morphology and permanent loss of proliferative potential. When HT-1080 cells were arrested by p21, they continued to grow exponentially in size and became hypertrophic with a 15-fold increase in the protein content per cell. These changes were mirrored by accumulation of GFP ( driven by CMV promoter) per cell, which also served as a marker of cellular hypertrophy. Preservation of proliferative potential ( competence) was measured by an increase in live cell number, when p21 was switched off. While modestly decreasing hypertrophy in p21-arresrted cells, rapamycin considerably preserved competence, converting senescence into quiescence. Preservation of proliferative potential ( competence) correlated with inhibition of S6 phosphorylation by rapamycin. When p21 was switched off, competent cells, by resuming proliferation, became progressively less hypertrophic. Preservation of proliferative potential is a sensitive and quantitative measure of suppression of mTOR-driven senescence.
引用
收藏
页码:1008 / 1016
页数:9
相关论文
共 31 条
[11]   p21Waf1/Cip1/Sdi1 mediates retinoblastoma protein degradation [J].
Broude, E. V. ;
Swift, M. E. ;
Vivo, C. ;
Chang, B-D ;
Davis, B. M. ;
Kalurupalle, S. ;
Blagosklonny, M. V. ;
Roninson, I. B. .
ONCOGENE, 2007, 26 (48) :6954-6958
[12]   Senescent cells, tumor suppression, and organismal aging: Good citizens, bad neighbors [J].
Campisi, J .
CELL, 2005, 120 (04) :513-522
[13]  
Chang BD, 1999, CANCER RES, V59, P3761
[14]   p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells [J].
Chang, BD ;
Broude, EV ;
Fang, J ;
Kalinichenko, TV ;
Abdryashitov, R ;
Poole, JC ;
Roninson, IB .
ONCOGENE, 2000, 19 (17) :2165-2170
[15]   Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence [J].
Coppe, Jean-Philippe ;
Kauser, Katalin ;
Campisi, Judith ;
Beausejour, Christian M. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (40) :29568-29574
[16]   Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor [J].
Coppe, Jean-Philippe ;
Patil, Christopher K. ;
Rodier, Francis ;
Sun, Yu ;
Munoz, Denise P. ;
Goldstein, Joshua ;
Nelson, Peter S. ;
Desprez, Pierre-Yves ;
Campisi, Judith .
PLOS BIOLOGY, 2008, 6 (12) :2853-2868
[17]   Growth stimulation leads to cellular senescence when the cell cycle is blocked [J].
Demidenko, Zoya N. ;
Blagosklonny, Mikhail V. .
CELL CYCLE, 2008, 7 (21) :3355-3361
[18]   Pharmacologic inhibition of MEK and PI-3K converges on the mTOR/S6 pathway to decelerate cellular senescence [J].
Demidenko, Zoya N. ;
Shtutman, Michael ;
Blagosklonny, Mikhail V. .
CELL CYCLE, 2009, 8 (12) :1896-1900
[19]   Rapamycin decelerates cellular senescence [J].
Demidenko, Zoya N. ;
Zubova, Svetlana G. ;
Bukreeva, Elena I. ;
Pospelov, Valery A. ;
Pospelova, Tatiana V. ;
Blagosklonny, Mikhail V. .
CELL CYCLE, 2009, 8 (12) :1888-1895
[20]   Induction of p53-dependent senescence by the MDM2 antagonist nutlin-3a in mouse cells of fibroblast origin [J].
Efeyan, Alejo ;
Ortega-Molina, Ana ;
Velasco-Miguel, Susana ;
Herranz, Daniel ;
Vassilev, Lyubomir T. ;
Serrano, Manuel .
CANCER RESEARCH, 2007, 67 (15) :7350-7357