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Insulin-like growth factor 1 receptor antibody induces rhabdomyosarcoma cell death via a process involving AKT and Bcl-xL

Oncogene volume 29, pages 6367–6377 (2010)Cite this article

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Abstract

Insulin-like growth factors (IGFs) and their receptor, IGF-1 receptor (IGF1R), have important roles in growth, development, stress response, aging and cancer. There are many agents that inhibit IGF1R in oncology clinical development, and in some cases, they have been associated with rapid tumor regression. However, it is not clear by which process these targeted agents induce cancer cell death and how to predict such tumor responses. Here, we showed that IGF1R antibody led to rapid cell death and tumor regression in some rhabdomyosarcoma (RMS) cells. Mechanistic analysis revealed a rapid onset of mitochondrial-dependent apoptosis, including mitochondrial depolarization, cytochrome C release and the activation of specific caspases. The antibody sensitive cells had greater dependence on AKT for maintaining downstream signaling and the expression of a constitutively active AKT, which restored AKT-signaling in these cells, inhibited anti-IGF1R induced cell death. Further analysis showed IGF1R antibody-induced hypophosphorylation of BAD and activation of downstream BAX. Interestingly, the examination of RMS cell lines and tumors revealed an inverse correlation between elevated IGF1R and Bcl-2 level (P=0.033), with the sensitive cells lacking Bcl-2 expression. The overexpression of BAD specific target, Bcl-xL, conferred resistance, whereas Bcl-xL knockdown sensitized cells lacking Bcl-2 to anti-IGF1R-induced cell death. We propose that RMS pathogenesis involves increased IGF1R expression that enhances AKT and Bcl-xL-mediated cell survival, and the blockage of IGF1R results in inhibition of survival signal from Bcl-xL and cell death in the sensitive Bcl-2 negative cells.

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Acknowledgements

We thank Dr Andrius Kazlauskas for providing the lentivirus expressing Bcl-xL, and Arnulfo Mendoza, Vanessa Moore, Susan Garfield and Barbara Taylor for excellent technical assistance. This research was supported by the Intramural Research Program of the US National Cancer Institute (NCI). This project was also funded in part with federal funds from the NCI, NIH, under contract N01-CO-12400.

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Authors and Affiliations

  1. Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    L H Mayeenuddin, Y Yu, Z Kang & L Cao

  2. Laboratory of Proteomics and Analytical Technologies,

    L H Mayeenuddin, Y Yu & Z Kang

  3. SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD, USA

    L H Mayeenuddin, Y Yu & Z Kang

  4. Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    L J Helman

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  1. L H Mayeenuddin
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Correspondence to L Cao.

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Mayeenuddin, L., Yu, Y., Kang, Z. et al. Insulin-like growth factor 1 receptor antibody induces rhabdomyosarcoma cell death via a process involving AKT and Bcl-xL. Oncogene 29, 6367–6377 (2010). https://doi.org/10.1038/onc.2010.364

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