کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5649470 | 1407125 | 2016 | 32 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
A Bifunctional Approach of Immunostimulation and uPAR Inhibition Shows Potent Antitumor Activity in Melanoma
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کلمات کلیدی
CTRLTLRuPAuPARRIG-ICXCL10C-X-C motif chemokine 10MEKiSmall interfering RNA - RNA تداخل کوچکsiRNA - siRNAToll-like receptor - تیالآرurokinase-type plasminogen activator - فعال کننده پلاسمینوژن نوع urokinaseretinoic acid-inducible gene I - ژن I القاء شده اسید رتینوئیکControl - کنترلUrokinase-type plasminogen activator receptor - گیرنده فعال کننده پلاسمینوژن نوع Urokinase
موضوعات مرتبط
علوم پزشکی و سلامت
پزشکی و دندانپزشکی
امراض پوستی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: A Bifunctional Approach of Immunostimulation and uPAR Inhibition Shows Potent Antitumor Activity in Melanoma A Bifunctional Approach of Immunostimulation and uPAR Inhibition Shows Potent Antitumor Activity in Melanoma](/preview/png/5649470.png)
چکیده انگلیسی
Significant advancements of mutation-based targeted therapy and immune checkpoint blockade have been achieved in melanoma. Nevertheless, acquired resistance and nonresponders to therapy require different strategies. An innovative approach is presented here that is based on the combination of innate immune system activation and simultaneous targeting of the oncogene urokinase-type plasminogen activator receptor (uPAR). We generated two triphosphate-conjugated siRNAs targeting uPAR (ppp-uPAR) by in vitro transcription. Specific uPAR knockdown and simultaneous activation of the retinoic acid-inducible gene 1 (RIG-I) was shown in different human melanoma cells, fibroblasts, and melanocytes. The compounds induced massive apoptosis in melanoma cells, whereas fibroblasts and melanocytes were less sensitive. The effects were less pronounced when the IFN receptor was blocked. Treatment with ppp-uPAR led to accumulation of p53 and induction of RIG-I-dependent proapoptotic signaling. The apoptotic effects induced by ppp-uPAR were maintained in melanoma cell lines that had acquired double resistance to B-RAF and MEK/extracellular signal-regulated kinase inhibition. Systemic intraperitoneal application of ppp-uPAR in nude mice significantly reduced growth of human melanoma xenografts and elicited a systemic innate immune response with increased serum cytokine levels. Our data suggest that ppp-uPAR represents a therapeutically attractive compound that may help overcome the strong therapy resistance of melanoma.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Investigative Dermatology - Volume 136, Issue 12, December 2016, Pages 2475-2484
Journal: Journal of Investigative Dermatology - Volume 136, Issue 12, December 2016, Pages 2475-2484
نویسندگان
Fanny Matheis, Markus V. Heppt, Saskia A. Graf, Peter Düwell, Claudia Kammerbauer, Achim Aigner, Robert Besch, Carola Berking,