Pharmacologic p53 Activation Blocks Cell Cycle Progression but Fails to Induce Senescence in Epithelial Cancer Cells
- 17 September 2009
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 7 (9), 1497-1509
- https://doi.org/10.1158/1541-7786.mcr-09-0144
Abstract
Cellular senescence is a stress-induced state of irreversible growth arrest thought to act as a barrier to cancer development. The p53 tumor suppressor is a critical mediator of senescence and recent in vivo studies have suggested that p53-induced senescence may contribute to tumor clearance by the immune system. Recently developed MDM2 antagonists, the nutlins, are effective p53 activators and potent antitumor agents in cells with functional apoptotic pathways. However, they only block cell cycle progression in cancer cells with compromised p53 apoptotic signaling. We use nutlin-3a as a selective probe to study the role of p53 activation in senescence using a panel of eight epithelial cancer cell lines and primary epithelial cells. Our results reveal that the MDM2 antagonist can induce a senescence-like state in all tested cell lines, but it is reversible and cells resume proliferation upon drug removal and normalization of p53 control. Retinoblastoma family members (pRb, p107, and p130) previously implicated in gene silencing during fibroblasts senescence were found down-regulated in cells with nutlin-induced senescence-like phenotype, suggesting a mechanism for its reversibility. Therefore, selective p53 pathway activation is insufficient for induction of true senescence in epithelial cells in vitro. However, elevated expression of several inflammatory cytokines in cancer cells with nutlin-induced senescence-like phenotype suggests a possible in vivo benefit of p53-activating therapies. (Mol Cancer Res 2009;7(9):1497–509)Keywords
This publication has 35 references indexed in Scilit:
- Cellular senescence: when bad things happen to good cellsNature Reviews Molecular Cell Biology, 2007
- Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomasNature, 2007
- Senescence in premalignant tumoursNature, 2005
- The signals and pathways activating cellular senescenceThe International Journal of Biochemistry & Cell Biology, 2005
- The p53 pathway: positive and negative feedback loopsOncogene, 2005
- Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad NeighborsCell, 2005
- Hallmarks of senescence in carcinogenesis and cancer therapyOncogene, 2004
- Surfing the p53 networkNature, 2000
- A biomarker that identifies senescent human cells in culture and in aging skin in vivo.Proceedings of the National Academy of Sciences of the United States of America, 1995
- The limited in vitro lifetime of human diploid cell strainsExperimental Cell Research, 1965