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

Cell. 2002 May 3;109(3):335-46. doi: 10.1016/s0092-8674(02)00734-1.

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 p16(INK4a). 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, p16(INK4a), 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Biomarkers
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Cellular Senescence / drug effects
  • Cellular Senescence / genetics
  • Cellular Senescence / physiology*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / physiology*
  • Cyclophosphamide / therapeutic use
  • Drug Resistance, Neoplasm / genetics
  • Drug Resistance, Neoplasm / physiology
  • Lymphoma, B-Cell / drug therapy
  • Lymphoma, B-Cell / etiology*
  • Lymphoma, B-Cell / genetics*
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mutation
  • Prognosis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-cbl
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p14ARF / genetics
  • Tumor Suppressor Protein p14ARF / physiology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / physiology*
  • Ubiquitin-Protein Ligases*

Substances

  • Antineoplastic Agents, Alkylating
  • Biomarkers
  • Cyclin-Dependent Kinase Inhibitor p16
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • Cyclophosphamide
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • Cbl protein, mouse