IGF-1R is a molecular determinant for response to p53 reactivation therapy in conjunctival melanoma

Autor: Tingting Lin, Leonard Girnita, Dawei Song, Eric Trocme, H. Zheng, Stefan Seregard, Naida Suleymanova, Caitrin Crudden, Ada Girnita, C. Worrall, Sonia Cismas
Přispěvatelé: Pathology, CCA - Cancer biology and immunology, Medicinal chemistry, AIMMS
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Oncogene. Nature Publishing Group
Oncogene, 41(4), 600-611. Nature Publishing Group
Song, D, Cismas, S, Crudden, C, Trocme, E, Worrall, C, Suleymanova, N, Lin, T, Zheng, H, Seregard, S, Girnita, A & Girnita, L 2022, ' IGF-1R is a molecular determinant for response to p53 reactivation therapy in conjunctival melanoma ', Oncogene, vol. 41, no. 4, pp. 600-611 . https://doi.org/10.1038/s41388-021-02111-x
Song, D, Cismas, S, Crudden, C, Trocme, E, Worrall, C, Suleymanova, N, Lin, T, Zheng, H, Seregard, S, Girnita, A & Girnita, L 2021, ' IGF-1R is a molecular determinant for response to p53 reactivation therapy in conjunctival melanoma ', Oncogene . https://doi.org/10.1038/s41388-021-02111-x
ISSN: 0950-9232
DOI: 10.1038/s41388-021-02111-x
Popis: As the p53 tumor suppressor is rarely mutated in conjunctival melanoma (CM), we investigated its activation as a potential therapeutic strategy. Preventing p53/Mdm2 interaction by Nutlin-3, the prototypical Mdm2 antagonist, or via direct siRNA Mdm2 depletion, increased p53 and inhibited viability in CM cell lines. The sensitivity to Nutlin-3 p53 reactivation with concomitant Mdm2 stabilization was higher than that achieved by siRNA, indicative of effects on alternative Mdm2 targets, identified as the cancer-protective IGF-1R. Nutlin-3 treatment increased the association between IGF-1R and β-arrestin1, the adaptor protein that brings Mdm2 to the IGF-1R, initiating receptor degradation in a ligand-dependent manner. Controlled expression of β-arrestin1 augmented inhibitory Nutlin-3 effects on CM survival through enhanced IGF-1R degradation. Yet, the effect of IGF-1R downregulation on cell proliferation is balanced by β-arrestin1-induced p53 inhibition. As mitomycin (MMC) is a well-established adjuvant treatment for CM, and it triggers p53 activation through genotoxic stress, we evaluated how these alternative p53-targeting strategies alter the cancer-relevant bioactivities of CM. In 2D and 3D in vitro models, Nutlin-3 or MMC alone, or in combination, reduces the overall cell tumor growth ~30%, with double treatment inhibition rate only marginally higher than single-drug regimens. However, histopathological evaluation of the 3D models revealed that Nutlin-3 was the most effective, causing necrotic areas inside spheroids and complete loss of nuclear staining for the proliferative marker Ki67. These findings were further validated in vivo; zebrafish xenografts demonstrate that Nutlin-3 alone has higher efficacy in restraining CM tumor cell growth and preventing metastasis. Combined, these results reveal that β-arrestin1 directs Mdm2 toward different substrates, thus balancing IGF-1R pro-tumorigenic and p53-tumor suppressive signals. This study defines a potent dual-hit strategy: simultaneous control of a tumor-promoter (IGF-1R) and tumor-suppressor (p53), which ultimately mitigates recurrent and metastatic potential, thus opening up targeted therapy to CM.
Databáze: OpenAIRE
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