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

Oncogene volume 41, pages 600–611 (2022)Cite this article

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A Correction to this article was published on 09 February 2023

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Abstract

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.

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Fig. 1: Effect of p53 reactivation on conjunctival melanoma cell viability.
Fig. 2: Effect of p53/Mdm2 reactivation on IGF-1R expression.
Fig. 3: β-Arrestin1 controls the IGF-1R downregulation initiated by p53/Mdm2 reactivation.
Fig. 4: β-arr1 as a determinant of Nutlin-3-induced IGF-1R degradation.
Fig. 5: Impact of alternative p53-activation strategies on CM malignant phenotype in vitro.
Fig. 6: Effect of alternative p53-activation strategies on CM malignant phenotype in vivo.

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Acknowledgements

We gratefully acknowledge Prof. Robert J Lefkowitz, Prof. Gerasimos Anastassiou, Prof. Rob J W de Keizer, Prof. Rolf Kiessling, and Prof. A. Ciechanover for providing cell lines and reagents. We thank Anna Malmerfelt at the histology core facility, Karolinska Institutet, for technical assistance. Research support was received from the Swedish Research Council, Swedish Cancer Society, The Swedish Childhood Cancer Foundation, Crown Princess Margareta’s Foundation for the Visually Impaired, Welander Finsen Foundation, King Gustaf V Jubilee Foundation, China Scholarship Council (Grant no. 201700260284), Stockholm Cancer Society, Stockholm County and Karolinska Institute. Schematics were partially created with BioRender.com.

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Authors and Affiliations

  1. Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

    Dawei Song, Sonia Cismas, Caitrin Crudden, Eric Trocme, Claire Worrall, Naida Suleymanova, Tingting Lin, Huiyuan Zheng, Ada Girnita & Leonard Girnita

  2. Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan, 1117, Amsterdam, The Netherlands

    Caitrin Crudden

  3. Ophthalmic Pathology and Oncology Service, St. Erik Eye Hospital, Stockholm, Sweden

    Eric Trocme, Stefan Seregard & Leonard Girnita

  4. Tianjin International Joint Research and Development Centre of Ophthalmology and Vision Science, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China

    Tingting Lin

  5. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    Huiyuan Zheng

  6. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Stefan Seregard

  7. Skin Cancer Center, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden

    Ada Girnita

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Contributions

Experimental design: DS, SC, CC, ET, CW, NS, TL, HZ, SS, AG, and LG. Development of methodology: DS, SC, CC, CW, and LG. Acquisition of data: DS, SC, CC, ET, CW, NS, TL, and HZ. Data curation and validation: DS, SC, CC, ET, CW, and LG. Analysis and interpretation of data: DS, SC, CC, ET, CW, NS, TL, HZ, SS, AG, and LG. Writing, review, and/or revision of the manuscript: DS, SC, CC, ET, CW, NS, SS, AG, and LG. Administrative, technical, or material support: DS, SC, CC, CW, SS, AG, and LG. Concept, project design, and study supervision: LG. All authors reviewed and approved the final manuscript.

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Song, D., Cismas, S., Crudden, C. et al. IGF-1R is a molecular determinant for response to p53 reactivation therapy in conjunctival melanoma. Oncogene 41, 600–611 (2022). https://doi.org/10.1038/s41388-021-02111-x

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