The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation.
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.
Beuvink
Iwan
I
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, P.O. Box 2543, CH-4058 Basel, Switzerland.
Boulay
Anne
A
Fumagalli
Stefano
S
Zilbermann
Frederic
F
Ruetz
Stephan
S
O'Reilly
Terence
T
Natt
Francois
F
Hall
Jonathan
J
Lane
Heidi A
HA
Thomas
George
G
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004357:Drug Synergism; D000068338:Everolimus; D006801:Humans; D009154:Mutation; D011132:Polyribosomes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin; D020123:Sirolimus