The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation

Iwan Beuvink; Anne Boulay; Stefano Fumagalli; Frederic Zilbermann; Stephan Ruetz; Terence O'Reilly; Francois Natt; Jonathan Hall; Heidi A Lane; George Thomas

doi:10.1016/j.cell.2004.12.040

The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation

Cell. 2005 Mar 25;120(6):747-59. doi: 10.1016/j.cell.2004.12.040.

Authors

Iwan Beuvink¹, Anne Boulay, Stefano Fumagalli, Frederic Zilbermann, Stephan Ruetz, Terence O'Reilly, Francois Natt, Jonathan Hall, Heidi A Lane, George Thomas

Affiliation

¹ Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, P.O. Box 2543, CH-4058 Basel, Switzerland.

PMID: 15797377
DOI: 10.1016/j.cell.2004.12.040

Abstract

Although DNA damaging agents have revolutionized chemotherapy against solid tumors, a narrow therapeutic window combined with severe side effects has limited their broader use. Here we show that RAD001 (everolimus), a rapamycin derivative, dramatically enhances cisplatin-induced apoptosis in wild-type p53, but not mutant p53 tumor cells. The use of isogenic tumor cell lines expressing either wild-type mTOR cDNA or a mutant that does not bind RAD001 demonstrates that the effects of RAD001 are through inhibition of mTOR function. We further show that RAD001 sensitizes cells to cisplatin by inhibiting p53-induced p21 expression. Unexpectedly, this effect is attributed to a small but significant inhibition of p21 translation combined with its short half-life. These findings provide the molecular rationale for combining DNA damaging agents with RAD001, showing that a general effect on a major anabolic process may dramatically enhance the efficacy of an established drug protocol in the treatment of cancer patients with solid tumors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Apoptosis / genetics
Apoptosis / physiology*
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / genetics
Cell Survival / drug effects
Cell Survival / genetics
Cell Survival / physiology
Cisplatin / pharmacology*
Cyclin-Dependent Kinase Inhibitor p21
DNA Damage / drug effects
DNA Damage / genetics
DNA Damage / physiology
Drug Synergism
Everolimus
Humans
Mutation
Polyribosomes / drug effects
Polyribosomes / genetics
Polyribosomes / metabolism
Protein Biosynthesis / drug effects*
Protein Biosynthesis / genetics
Protein Biosynthesis / physiology
Protein Kinases / genetics
Protein Kinases / metabolism*
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Sirolimus / analogs & derivatives*
Sirolimus / pharmacology*
TOR Serine-Threonine Kinases
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Antineoplastic Agents
CDKN1A protein, human
Cell Cycle Proteins
Cyclin-Dependent Kinase Inhibitor p21
RNA, Small Interfering
Tumor Suppressor Protein p53
Everolimus
Protein Kinases
MTOR protein, human
TOR Serine-Threonine Kinases
Cisplatin
Sirolimus