Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1 Journal Article
| Authors: | Ambrosini, G.; Sambol, E. B.; Carvajal, D.; Vassilev, L. T.; Singer, S.; Schwartz, G. K. |
| Article Title: | Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1 |
| Abstract: | MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53-/- cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wild-type E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73α and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy. © 2007 Nature Publishing Group All rights reserved. |
| Keywords: | cancer chemotherapy; controlled study; unclassified drug; human cell; dna-binding proteins; cisplatin; doxorubicin; drug potentiation; monotherapy; antineoplastic agents; mutant protein; animals; mice; dna damage; gene overexpression; carboplatin; apoptosis; proteasome; transcription initiation; 7 ethyl 10 hydroxycamptothecin; small interfering rna; rna interference; combination chemotherapy; cell differentiation; transcription, genetic; antineoplastic activity; cancer cell culture; cytotoxicity; tumor cells, cultured; wild type; protein p53; nuclear proteins; correlation analysis; regulatory mechanism; tumor suppressor proteins; tumor suppressor protein p53; down regulation; piperazines; nerve sheath tumor; peripheral nerve tumor; drug sensitivity; proto-oncogene proteins c-bcl-2; transcription factor e2f1; protein inhibitor; liposarcoma; imidazoles; drug dose sequence; protein mdm2; proto-oncogene proteins c-mdm2; mdm2; e2f1; sarcoma cell; protein p73; e2f1 transcription factor; nutlin-3a; nutlin 3a; protein noxa; protein p73alpha; binding kinetics |
| Journal Title: | Oncogene |
| Volume: | 26 |
| Issue: | 24 |
| ISSN: | 0950-9232 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2007-05-24 |
| Start Page: | 3473 |
| End Page: | 3481 |
| Language: | English |
| DOI: | 10.1038/sj.onc.1210136 |
| PUBMED: | 17146434 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 64" - "Export Date: 17 November 2011" - "CODEN: ONCNE" - "Source: Scopus" |
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