Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells
Targeted Activation of Innate Immunity for Therapeutic Induction of Autophagy and Apoptosis in Melanoma Cells
Tormo, D., et al. Cancer Cell. 16, 103–114 (2009).
Speaker : Cheng-Yu Wang (王政育) Time: 15:10~16:00, Mar.17, 2010
Commentator: Dr. Hsiao-Sheng Liu (劉校生老師) Place: Room 601
Abstract:
Melanoma is one of the less common types of skin cancer but it is the major cause of skin cancer related deaths. It has the poor prognosis at late stage because of multiple genetic and epigenetic alterations that promote its metastasis and resistance. The average survival of patient with metastasis is less than 10 months. In this paper, the author shows that authphagy may be the newly potential approach of melanoma in the future. Autophagy is an evolutionarily conserved fundamental intracellular degradative process operating as a homeostatic mechanism. The author found that [pIC]PEI which is the dsRNA mimics pIC delivered by polyethyleneimine (PEI) could induce autophagy at melanoma cells. PEI is a polycation that favors endosomal uptake and cytosolic release. There were GFP-LC3 puncta and autophagosome at [pIC]PEI treated melanoma cells but not at pIC or PEI alone treated. The autophay induced by [pIC]PEI was persistent and was invariably followed by cell death. The [pIC]PEI induced cell death was less sensitive at Atg5-/-MEFs(mouse embryonic fibroblasts) or chloroquine (a lysosome inhibitor) treated melanoma cells. An autophagosome-lysosome fusion is required by the [pIC]PEI mediated cell death. [pIC]PEI links autophagy to apoptotic caspases, an early but persistent autophagy was induced followed by a late apoptotic program. Furthermore, the author found MDA-5(melanoma differentiation-associated gene-5) is a sensor for [pIC]PEI. The [pIC]PEI induced melanoma cells death was reduced by knock-down of MDA-5. An apoptosis-associated processing of MDA-51 was found in [pIC]PEI treated melanoma cells. With the cDNA microarray of proapoptotic factors, NOXA was identified as the target upregulated by [pIC]PEI. A MDA-5 driven NOXA-dependent cell death was induced by [pIC]PEI. [pIC]PEI also shows the inhibition of metastatic melanoma dissemination in immunocompetent and immunosuppressed mice. In conclusion, this study reveals that dsRNA helicases can be the therapeutic targets cause the autophagy and apoptosis of melanoma cells. This might overcome the inherent resistance of melanoma cells to current treatments.
References:
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