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JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling

Background: JWA gene is known to down-regulate SP1 and reduces the expression level of Integrin αvβ3. Here, we identified a functional polypeptide (JP1) based on the active fragment of the JWA protein to suppress melanoma growth and metastasis by inhibiting the Integrin αvβ3. Methods: We conducted a...

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Autores principales: Cui, Jiahua, Shu, Chuanjun, Xu, Jin, Chen, Dongyin, Li, Jin, Ding, Kun, Chen, Minjuan, Li, Aiping, He, Jingdong, Shu, Yongqian, Yang, Liuqing, Zhang, Ruiwen, Zhou, Jianwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381750/
https://www.ncbi.nlm.nih.gov/pubmed/32724456
http://dx.doi.org/10.7150/thno.45843
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author Cui, Jiahua
Shu, Chuanjun
Xu, Jin
Chen, Dongyin
Li, Jin
Ding, Kun
Chen, Minjuan
Li, Aiping
He, Jingdong
Shu, Yongqian
Yang, Liuqing
Zhang, Ruiwen
Zhou, Jianwei
author_facet Cui, Jiahua
Shu, Chuanjun
Xu, Jin
Chen, Dongyin
Li, Jin
Ding, Kun
Chen, Minjuan
Li, Aiping
He, Jingdong
Shu, Yongqian
Yang, Liuqing
Zhang, Ruiwen
Zhou, Jianwei
author_sort Cui, Jiahua
collection PubMed
description Background: JWA gene is known to down-regulate SP1 and reduces the expression level of Integrin αvβ3. Here, we identified a functional polypeptide (JP1) based on the active fragment of the JWA protein to suppress melanoma growth and metastasis by inhibiting the Integrin αvβ3. Methods: We conducted a series of melanoma growth and metastasis mouse models to evaluate anti-melanoma effect of JP1 peptide. (18)F-labeled JP1 ((18)F-NFP-JP1) was detected by Micro-PET assay to demonstrate drug biodistribution. Toxicity test in cynomolgus monkeys and pharmacokinetic studies in rats were done to assess the druggability. The expression of MEK1/2, NEDD4L, SP1 and Integrin αvβ3 were detected in vitro and vivo models. Results: The peptide JP1 with the best anticancer effect was obtained. Micro-PET assay showed that JP1 specifically targeting to melanoma cells in vivo. JP1 inhibited melanoma growth, metastasis, and prolonged the survival of mouse. JP1 reduced the dosage and toxicity in combination with DTIC in melanoma xenograft and allograft mouse models. Cynomolgus monkey toxicity test showed no observed adverse effect level (NOAEL) of JP1 was 150 mg/kg. Mechanistically, JP1 was shown to activate p-MEK1/2 and triggered SP1 ubiquitination in melanoma cells. NEDD4L, an E3 ubiquitin ligase, was activated by p-MEK1/2 and to ubiquitinate SP1 at K685 site, resulting in subsequent degradation. Conclusions: JP1 was developed as a novel peptide that indicated therapeutic roles on proliferation and metastasis of melanoma through the NEDD4L-SP1-Integrin αvβ3 signaling.
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spelling pubmed-73817502020-07-27 JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling Cui, Jiahua Shu, Chuanjun Xu, Jin Chen, Dongyin Li, Jin Ding, Kun Chen, Minjuan Li, Aiping He, Jingdong Shu, Yongqian Yang, Liuqing Zhang, Ruiwen Zhou, Jianwei Theranostics Research Paper Background: JWA gene is known to down-regulate SP1 and reduces the expression level of Integrin αvβ3. Here, we identified a functional polypeptide (JP1) based on the active fragment of the JWA protein to suppress melanoma growth and metastasis by inhibiting the Integrin αvβ3. Methods: We conducted a series of melanoma growth and metastasis mouse models to evaluate anti-melanoma effect of JP1 peptide. (18)F-labeled JP1 ((18)F-NFP-JP1) was detected by Micro-PET assay to demonstrate drug biodistribution. Toxicity test in cynomolgus monkeys and pharmacokinetic studies in rats were done to assess the druggability. The expression of MEK1/2, NEDD4L, SP1 and Integrin αvβ3 were detected in vitro and vivo models. Results: The peptide JP1 with the best anticancer effect was obtained. Micro-PET assay showed that JP1 specifically targeting to melanoma cells in vivo. JP1 inhibited melanoma growth, metastasis, and prolonged the survival of mouse. JP1 reduced the dosage and toxicity in combination with DTIC in melanoma xenograft and allograft mouse models. Cynomolgus monkey toxicity test showed no observed adverse effect level (NOAEL) of JP1 was 150 mg/kg. Mechanistically, JP1 was shown to activate p-MEK1/2 and triggered SP1 ubiquitination in melanoma cells. NEDD4L, an E3 ubiquitin ligase, was activated by p-MEK1/2 and to ubiquitinate SP1 at K685 site, resulting in subsequent degradation. Conclusions: JP1 was developed as a novel peptide that indicated therapeutic roles on proliferation and metastasis of melanoma through the NEDD4L-SP1-Integrin αvβ3 signaling. Ivyspring International Publisher 2020-07-01 /pmc/articles/PMC7381750/ /pubmed/32724456 http://dx.doi.org/10.7150/thno.45843 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Cui, Jiahua
Shu, Chuanjun
Xu, Jin
Chen, Dongyin
Li, Jin
Ding, Kun
Chen, Minjuan
Li, Aiping
He, Jingdong
Shu, Yongqian
Yang, Liuqing
Zhang, Ruiwen
Zhou, Jianwei
JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling
title JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling
title_full JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling
title_fullStr JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling
title_full_unstemmed JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling
title_short JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling
title_sort jp1 suppresses proliferation and metastasis of melanoma through mek1/2 mediated nedd4l-sp1-integrin αvβ3 signaling
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381750/
https://www.ncbi.nlm.nih.gov/pubmed/32724456
http://dx.doi.org/10.7150/thno.45843
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