E2F-1 transcriptional activity is a critical determinant of Mdm2 antagonist-induced apoptosis in human tumor cell lines

Kitagawa, Mayumi; Aonuma, Masashi; Lee, S H; Fukutake, Setsuko; McCormick, Frank

doi:10.1038/onc.2008.164

Cited by 84 publications

(88 citation statements)

References 30 publications

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“…Furthermore, no correlation was found between downregulation of Mdm4 and sensitivity on Nutlin-3 treatment. These findings confirm a recent report in which it was shown that neither endogenous Mdm2 nor Mdm4 levels in cancer cells correlate with Nutlin-3 sensitivity (Kitagawa et al, 2008). These authors also proposed that E2F-1 activity is a critical determinant for Nutlin-3-induced apoptosis, which would explain why retinoblastoma cell lines are sensitive to Nutlin-3-induced apoptosis in spite of expressing high levels of Mdm4 (Laurie et al, 2006).…”

Section: Regulation Of Drug Response By Mdm4supporting

confidence: 90%

“…These authors also proposed that E2F-1 activity is a critical determinant for Nutlin-3-induced apoptosis, which would explain why retinoblastoma cell lines are sensitive to Nutlin-3-induced apoptosis in spite of expressing high levels of Mdm4 (Laurie et al, 2006). Furthermore, these authors show that the downregulation of E2F-1 observed in wild-type p53 cells on Nutlin-3 treatment is dependent on pRB expression (Kitagawa et al, 2008). As treatment with Nutlin-3 strongly reduced E2F-1 levels in the breast cancer cells tested here (data not shown), an involvement of E2F-1 activity in the distinct sensitivity of the cell lines for Nutlin-3 seems unlikely.…”

Section: Regulation Of Drug Response By Mdm4mentioning

confidence: 92%

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Role of Mdm4 in drug sensitivity of breast cancer cells

et al. 2010

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The p53 tumor suppressor protein is frequently mutated in human tumors. It is thought that the p53 pathway is indirectly impaired in the remaining tumors, for example by overexpression of its important regulators Mdm2 and Mdm4, making them attractive targets for the development of anti-cancer agents. Recent studies have suggested that Mdm4 levels determine the sensitivity of tumor cells for anti-cancer therapy. To investigate this possibility, we studied the drug sensitivity of several breast cancer cell lines containing wild-type p53, but expressing different Mdm4 levels. We show that endogenous Mdm4 levels can affect the sensitivity of breast cancer cells to anti-cancer agents, but in a cell line-dependent manner and depending on an intact apoptotic response. Furthermore, treatment with the non-genotoxic agent Nutlin-3 sensitizes cells for doxorubicin, showing that activation of p53 by targeting its regulators is an efficient strategy to decrease cell viability of breast cancer cells. These results confirm a function of Mdm4 in determining the efficacy of chemotherapeutic agents to induce apoptosis of cancer cells in a p53-dependent manner, although additional undetermined factors also influence the drug response. Targeting Mdm4 to sensitize tumor cells for chemotherapeutic drugs might be a strategy to effectively treat tumors harboring wild-type p53.

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Section: Regulation Of Drug Response By Mdm4supporting

confidence: 90%

Section: Regulation Of Drug Response By Mdm4mentioning

confidence: 92%

Role of Mdm4 in drug sensitivity of breast cancer cells

et al. 2010

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“…Particularly, loss of RB has been shown to result in a proclivity toward cell death mediated by p53 (Morgenbesser et al, 1994). In addition, there is evidence for cooperation between increased E2F activity and exposure to Nutlin-3a leading to increased rates of p53-mediated apoptosis (Kitagawa et al, 2008). Proteins were harvested from exponentially growing cells and subjected to immunoblot for RB and downstream target proteins.…”

Section: Rb Loss Cooperates With Ras-mediated Tumor Growthmentioning

confidence: 99%

Modeling the effect of the RB tumor suppressor on disease progression: dependence on oncogene network and cellular context

et al. 2009

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The retinoblastoma tumor suppressor, RB, is a key regulator of cellular proliferation that is functionally inactivated at high frequency in human cancer. Although RB has been extensively studied with regard to tumor etiology, loss of tumor-suppressor function often occurs relatively late in tumor progression. Therefore, inactivation of RB could have a profound impact on the behavior of tumors driven by discrete oncogenes. Here, collaboration between Ras or c-Myc deregulation and RB functional state was investigated in a model of conditional genetic deletion to decipher the effects related to disease progression. These studies showed that RB loss had a robust impact on mitogen dependence, anchorage dependence and overall survival, which was significantly modified by oncogene activation. Specifically, RB deficiency predisposed c-Myc-expressing cells to cell death and reduced overall tumorigenic proliferation. In contrast, RB deficiency exacerbated the tumorigenic behavior of Ras-transformed cells in both the model system and human tumor cell lines. As these tumors exhibited highly aggressive behavior, the possibility of exploiting the intrinsic sensitivity to cell death with RB loss was evaluated. Particularly, although Ras-transformed, RB-deficient cells bypassed the G1-checkpoint elicited by pharmacological activation of the p53 pathway, they were also highly sensitized to cell death. Altogether, these data suggest that the impact of RB deletion is dependent on the oncogene milieu, and can directly contribute to transformed phenotypes and response to therapeutic intervention.

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“…In addition, various studies have shown that very high doses of nutlin-3a, at the range of 20 mM to 430 mM, can induce cytotoxicity and inhibit the growth of cancer cells harbouring a nonfunctional mt p53 gene, through effects on partner proteins of Mdm2 other than p53, including the p53-related protein p73 and E2F1. [34][35][36] As these targets also can be affected by genotoxic chemotherapeutic agents, we investigated the potential effect of nutlin-3a on the anti-tumour activity of doxorubicin against ALK þ ALCL cells harbouring nonfunctional, mt p53.…”

Section: P53 Reactivation In Alcl E Drakos Et Almentioning

confidence: 99%

The therapeutic potential of p53 reactivation by nutlin-3a in ALK+ anaplastic large cell lymphoma with wild-type or mutated p53

et al. 2009

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p53 is expressed frequently, but is rarely mutated in anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) tumours. Nutlin-3a is a recently developed small molecule that targets Mdm2, a critical negative regulator of p53, and disrupts the p53-Mdm2 interaction resulting in p53 stabilization and activation. We show that nutlin-3a activates p53 in ALK þ ALCL cells carrying a wild type (wt) or mutated but partially functional p53 gene resulting in p53-dependent cell-cycle arrest and apoptosis. Cell-cycle arrest was associated with upregulation of the cyclin-dependent kinase inhibitor p21. Nutlin-3a-induced apoptotic cell death was accompanied by Bax and Puma upregulation, downregulation of Bcl-xl, survivin, and caspase-3 cleavage, and this was reduced when p53-dependent transactivation activity was inhibited by pifithrin-a, or when pifithrin-l was used to inhibit direct p53 targeting of mitochondria. Nutlin-3a sensitized the activation of the extrinsic apoptotic pathway in wt-p53 ALK þ ALCL cells, in part, through upregulation of DR-5 and downregulation of c-Flip S/L , and was synergistic with TRAIL in cell death induction. In addition, nutlin-3a treatment enhanced doxorubicin cytotoxicity against ALK þ ALCL cells harbouring mt p53, and this was associated with p73 upregulation. These data suggest that disruption of the p53-mdm2 interaction by nutlin-3a offers a novel therapeutic approach for ALK þ ALCL patients.

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E2F-1 transcriptional activity is a critical determinant of Mdm2 antagonist-induced apoptosis in human tumor cell lines

Cited by 84 publications

References 30 publications

Role of Mdm4 in drug sensitivity of breast cancer cells

Role of Mdm4 in drug sensitivity of breast cancer cells

Modeling the effect of the RB tumor suppressor on disease progression: dependence on oncogene network and cellular context

The therapeutic potential of p53 reactivation by nutlin-3a in ALK+ anaplastic large cell lymphoma with wild-type or mutated p53

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