TY - JOUR
T1 - The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML
AU - Kojima, K.
AU - Shimanuki, M.
AU - Shikami, M.
AU - Samudio, I. J.
AU - Ruvolo, V.
AU - Corn, P.
AU - Hanaoka, N.
AU - Konopleva, M.
AU - Andreeff, M.
AU - Nakakuma, H.
N1 - Funding Information:
We acknowledge Dr Maria Soengas of Department of Dermatology, University of Michigan, Ann Arbor, MI, USA for kindly providing retrovirus encoding p53-specific shRNA. KK was supported in part by grants from the Kanae Foundation For Life and Socio-Medical Science and Novartis Foundation (Japan) for the Promotion of Science, MA by the Paul and Mary Haas Chair in Genetics and a grant from NIH, CA55164 and CA100632.
PY - 2008
Y1 - 2008
N2 - Activation of the phosphatidylinositol-3 kinase/Akt/mammalian target of the rapamycin (PI3K/Akt/mTOR) pathway and inactivation of wild-type p53 by murine double minute 2 homologue (Mdm2) overexpression are frequent molecular events in acute myeloid leukemia (AML). We investigated the interaction of PI3K/Akt/mTOR and p53 pathways after their simultaneous blockade using the dual PI3K/mTOR inhibitor PI-103 and the Mdm2 inhibitor Nutlin-3. We found that PI-103, which itself has modest apoptogenic activity, acts synergistically with Nutlin-3 to induce apoptosis in a wild-type p53-dependent fashion. PI-103 synergized with Nutlin-3 to induce Bax conformational change and caspase-3 activation, despite its inhibitory effect on p53 induction. The PI-103/Nutlin-3 combination caused profound dephosphorylation of 4E-BP1 and decreased expression of many proteins including Mdm2, p21, Noxa, Bcl-2 and survivin, which can affect mitochondrial stability. We suggest that PI-103 actively enhances downstream p53 signaling and that a combination strategy aimed at inhibiting PI3K/Akt/mTOR signaling and activating p53 signaling is potentially effective in AML, where TP53 mutations are rare and downstream p53 signaling is intact.
AB - Activation of the phosphatidylinositol-3 kinase/Akt/mammalian target of the rapamycin (PI3K/Akt/mTOR) pathway and inactivation of wild-type p53 by murine double minute 2 homologue (Mdm2) overexpression are frequent molecular events in acute myeloid leukemia (AML). We investigated the interaction of PI3K/Akt/mTOR and p53 pathways after their simultaneous blockade using the dual PI3K/mTOR inhibitor PI-103 and the Mdm2 inhibitor Nutlin-3. We found that PI-103, which itself has modest apoptogenic activity, acts synergistically with Nutlin-3 to induce apoptosis in a wild-type p53-dependent fashion. PI-103 synergized with Nutlin-3 to induce Bax conformational change and caspase-3 activation, despite its inhibitory effect on p53 induction. The PI-103/Nutlin-3 combination caused profound dephosphorylation of 4E-BP1 and decreased expression of many proteins including Mdm2, p21, Noxa, Bcl-2 and survivin, which can affect mitochondrial stability. We suggest that PI-103 actively enhances downstream p53 signaling and that a combination strategy aimed at inhibiting PI3K/Akt/mTOR signaling and activating p53 signaling is potentially effective in AML, where TP53 mutations are rare and downstream p53 signaling is intact.
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U2 - 10.1038/leu.2008.158
DO - 10.1038/leu.2008.158
M3 - Article
C2 - 18548093
AN - SCOPUS:51649098950
SN - 0887-6924
VL - 22
SP - 1728
EP - 1736
JO - Leukemia
JF - Leukemia
IS - 9
ER -