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標題: Mcl-1 determines the imiquimod-induced apoptosis but not imiquimod-induced autophagy in skin cancer cells
作者: Huang, S.W.
Chang, C.C.
Lin, C.C.
Tsai, J.J.
Chen, Y.J.
Wu, C.Y.
Liu, K.T.
Shieh, J.J.
關鍵字: Imiquimod;Mcl-1;Skin cancer cells;Basal cell carcinoma;Apoptosis;Autophagy;response modifier imiquimod;carcinoma-cells;bcl-2 family;in-vivo;translation;death;expression;survival;tlr7;gene
Project: Journal of Dermatological Science
期刊/報告no:: Journal of Dermatological Science, Volume 65, Issue 3, Page(s) 170-178.
Background: Imiquimod had been shown to induce apoptosis and autophagy in several skin cancer cells, especially basal cell carcinoma (BCC) cells. Objective: We evaluate the molecular mechanisms of imiquimod-induced apoptosis and autophagy in skin cancer cell lines. Methods: The Mcl-1, Bcl-2 and Bcl-xL proteins were determined by immunoblotting. The Mcl-1 mRNA level was examined by RT-PCR and real-time PCR. The mechanisms of imiquimod-induced decrease in Mcl-1 protein were evaluated by addition of cycloheximide. MG132 proteasome inhibitor or pan-caspase inhibitor. The phosphorylation of eIF4E, 4E-BP1 and eEF2 in imiquimod treated cells were examined by immunoblotting. The imiquimod-induced apoptosis and autophagy were evaluated in Mcl-1-overexpressing cells by XTT test, mitochondrial membrane potential measurement, DNA content assay, LC3 immunoblotting, EGFP-LC3 puncta formation and quantification of acidic vesicular organelle with acridine orange staining. Results: The decrease in the Mcl-1 protein level was faster and stronger than the decrease in Bcl-2 and Bcl-xL in imiquimod-treated skin cancer cells. The imiquimod-induced decrease in Mcl-1 protein was not caused by blocked transcription or the promotion of degradation but was associated with inactivation of translation factors in BCC cells. The Mcl-1-overexpressing BCC cells were more resistant to intrinsic cellular apoptosis than control BCC cells during imiquimod treatment. Mcl-1 overexpression in BCC cells resulted in the basal activation of autophagy but did not modulate imiquimod-induced autophagy or rescue imiquimod-induced autophagic cell death in BCC cells. Conclusions: Imiquimod may rapidly downregulate Mcl-1 protein levels by inhibiting translation in skin cancer cells. Mcl-1 may act to protect against apoptosis but not autophagy and autophagic cell death during imiquimod treatment in skin cancer cells. (C) 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
ISSN: 0923-1811
DOI: 10.1016/j.jdermsci.2011.11.001
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