A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy.
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.
Schmitt
Clemens A
CA
Cold Spring Harbor Laboratory, 1 Bungtown Road, New York 11724, USA.
Fridman
Jordan S
JS
Yang
Meng
M
Lee
Soyoung
S
Baranov
Eugene
E
Hoffman
Robert M
RM
Lowe
Scott W
SW
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015415:Biomarkers; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D003520:Cyclophosphamide / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D003520:Cyclophosphamide; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C493849:Cbl protein, mouse