Editors' ChoiceCancer

Targeting the MDM2-p53 Interaction

Science's STKE  14 Feb 2006:
Vol. 2006, Issue 322, pp. tw56
DOI: 10.1126/stke.3222006tw56

Nutlins are cis imidazoline compounds that inhibit the interaction between the tumor suppressor p53 and the E3 ubiquitin ligase MDM2 that targets p53 for degradation. Tovar et al. show that in 10 different cancer cells lines, which have wild-type p53, nutlin-3a induces cell cycle arrest; however, the ability of nutlin-3a to induce apoptosis in different cell lines varied. DNA damage, which activates p53-dependent and p53-independent pathways, induced apoptosis in representative cell lines from the low, medium, and high apoptotic groups, indicating that the differential sensitivity to apoptosis induced by nutlin-3a was due to defects in the p53-dependent apoptotic pathway. The osteosarcoma cell line SJSA-1, which has a ~25-fold amplification of the mdm2 gene, was the most sensitive to nutlin-3a-induced apoptosis. To verify that mdm2 amplification was responsible, two additional osteosarcoma cell lines were analyzed--MHM, which has a ~10-fold amplification of the mdm2 gene, and U2OS, which has a single copy of the mdm2 gene. All three osteosarcoma cells lines exhibited cell cycle arrest when exposed to nutlin-3a; however, the sensitivity to induction of apoptosis correlated with mdm2 genotype, with the U2OS cells resistant to nutlin-3a-induced apoptosis. Microarray analysis was used to compare the transcriptional profiles of nutlin-3a-treated cells with amplified mdm2 to those with a single copy of mdm2. One of the differences was that proapoptotic genes, such as puma, noxa, and bax, were more strongly stimulated in the cells with the mdm2 amplification in response to nutlin-3a treatment. Finally, nutlin-3a caused tumor regression in nude mice with MHM and SJSA-1 tumors and halted the growth of tumors that had normal MDM2 and p53. These results suggest that (i) nutlins may be effective clinically, especially for tumors with mdm2 amplification, and (ii) cancer cells with normal p53 may have defects in the p53 apoptotic pathway, and nutlins may be useful tools for discerning these downstream defects.

C. Tovar, J. Rosinski, Z. Filipovic, B. Higgins, K. Kolinsky, H. Hilton, X. Zhao, B. T. Vu, W. Qing, K. Packman, O. Myklebost, D. C. Heimbrook, L. T. Vassilev, Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: Implications for therapy. Proc. Natl. Acad. Sci. U.S.A. 103, 1888-1893 (2006). [Abstract] [Full Text]