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.

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