Cell
Volume 109, Issue 3, 3 May 2002, Pages 335-346
Journal home page for Cell

Article
A Senescence Program Controlled by p53 and p16INK4a Contributes to the Outcome of Cancer Therapy

https://doi.org/10.1016/S0092-8674(02)00734-1Get rights and content
Under an Elsevier user license
open archive

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.

Cited by (0)

4

Present address: Max-Delbrück-Center for Molecular Medicine and Charité/Campus Virchow-Hospital, Department of Hematology/Oncology, Humboldt University, D-13353 Berlin, Germany.