Abstract 666: Regulation of IGF-1 signaling by lysosomal cathepsins in neuroblastoma
| Autor: | Guizhen Lu, Mehrnoosh Soori, Donna M. Cartledge, Lisa Glazewski, Robert W. Mason |
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| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | Cancer Research. 70:666-666 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am10-666 |
| Popis: | Neuroblastoma is the most common extracranial solid tumor of childhood. Despite intensive combination therapies, the survival rate for children diagnosed with high-risk neuroblastoma remains below 40%, with surviving children suffering from severe side-effects of aggressive surgery, cytotoxic chemotherapy and radiation. We show that specific inhibition of a group of lysosomal proteases results in accumulation of autophagic vacuoles and eventual apoptosis of neuroblastoma cell lines. Cell death is not caused in breast and prostate cancer cell lines or mouse primary fibroblasts, indicating specificity of the apoptotic response in neuroblastoma. In this study we have examined mechanisms by which inhibition of these proteases can lead to the specific death of these tumors. IGF-1 signaling is essential for cellular proliferation, survival, and apoptotic resistance. We found that in neuroblastoma cells IGF-1 signaling is impaired by inhibition of cathepsins B and L. Western blotting shows that lower molecular weight fragments of the IGF-1 receptor beta subunit accumulate in inhibitor-treated cells, indicating that lysosomal proteases are essential for the complete the degradation of the IGF-1 receptor. Phosphorylation and activation of full-length IGF-1 receptor was not modified by inhibitor treatment, but phosphorylation and activation of MAPK and Akt (downstream effectors of IGF-1 receptor signaling) was greatly diminished. Fractionation of cellular lysates showed that the IGF-1R β fragments accumulate in compartments that contain a cleaved form of LC-3, a marker of autophagic vacuoles. Intermediates of the IGF-1 signaling cascade were also sequestered within these compartments, and significantly depleted in the cytoplasm. We conclude that inhibition of lysosomal proteases results in sequestration of critical components of the cell signaling transduction pathway, causing cell death by uncoupling of cell surface and endosomal signaling from intracellular effector signals. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 666. |
| Databáze: | OpenAIRE |
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