A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy

Item Type:	Article
Title:	A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy
Creators Name:	Schmitt, C.A. and Fridman, J.S. and Yang, M. and Lee, S. and Baranov, E. and Hoffman, R.M. and Lowe, S.W.
Abstract:	p53 and INK4a/ARF mutations promote tumorigenesis and drug resistance, in part, by disabling apoptosis. We show that primary murine lymphomas also respond to chemotherapy by engaging a senescence program controlled by p53 and p16INK4a. Hence, tumors with p53 or INK4a/ARF mutations—but not those lacking ARF alone—respond poorly to cyclophosphamide therapy in vivo. Moreover, tumors harboring a Bcl2-mediated apoptotic block undergo a drug-induced cytostasis involving the accumulation of p53, p16INK4a, and senescence markers, and typically acquire p53 or INK4a mutations upon progression to a terminal stage. Finally, mice bearing tumors capable of drug-induced senescence have a much better prognosis following chemotherapy than those harboring tumors with senescence defects. Therefore, cellular senescence contributes to treatment outcome in vivo.
Keywords:	Alkylating Antineoplastic Agents, Apoptosis, B-Cell Lymphoma, Biomarkers, Cell Aging, Cell Survival, Cultured Tumor Cells, Cyclin-Dependent Kinase Inhibitor p16, Cyclophosphamide, Knockout Mice, Mutant Strains Mice, Mutation, Neoplasm Drug Resistance, Prognosis, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-cbl, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Animals, Mice
Source:	Cell
ISSN:	0092-8674
Publisher:	Cell Press
Volume:	109
Number:	3
Page Range:	335-346
Date:	3 May 2002
Official Publication:	https://doi.org/10.1016/S0092-8674(02)00734-1
PubMed:	View item in PubMed

Repository Staff Only: item control page