Ablation of key oncogenic pathways by RITA-reactivated p53 is required for efficient apoptosis.
Targeting "oncogene addiction" is a promising strategy for anticancer therapy. We report a potent inhibition of crucial oncogenes by p53 upon reactivation by small-molecule RITA in vitro and in vivo. RITA-activated p53 unleashes the transcriptional repression of antiapoptotic proteins Mcl-1, Bcl-2, MAP4, and survivin; blocks the Akt pathway on several levels; and downregulates c-Myc, cyclin E, and beta-catenin. p53 ablates c-Myc expression via several mechanisms at the transcriptional and posttranscriptional level. We show that the threshold for p53-mediated transrepression of survival genes is higher than for transactivation of proapoptotic targets. Inhibition of oncogenes by p53 reduces the cell's ability to buffer proapoptotic signals and elicits robust apoptosis. Our study highlights the role of transcriptional repression for p53-mediated tumor suppression.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177, Stockholm, Sweden.
Vera V
VV
Grinkevich
Fedor
F
Nikulenkov
Yao
Y
Shi
Martin
M
Enge
Wenjie
W
Bao
Alena
A
Maljukova
Angela
A
Gluch
Alexander
A
Kel
Olle
O
Sangfelt
Galina
G
Selivanova
D017209:Apoptosis; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005663:Furans / Q000494:pharmacology; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D005663:Furans; D008869:Microtubule-Associated Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt