Theranostics 2020; 10(18):8036-8050. doi:10.7150/thno.45843

Research Paper

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

Jiahua Cui1,2*, Chuanjun Shu3*, Jin Xu1,2, Dongyin Chen4, Jin Li5, Kun Ding1,2, Minjuan Chen1,2, Aiping Li1,2, Jingdong He5, Yongqian Shu2,6, Liuqing Yang7, Ruiwen Zhang8, Jianwei Zhou1,2✉

1. Department of Molecular Cell Biology & Toxicology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
2. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing 211166, China.
3. Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China
4. Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
5. Department of Oncology, the Affiliated No. 1 Hospital of Nanjing Medical University, Huaian, Jiangsu Province, China.
6. Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
7. Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8. Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204, USA.
*The authors contributed equally to this study.

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Citation:
Cui J, Shu C, Xu J, Chen D, Li J, Ding K, Chen M, Li A, He J, Shu Y, Yang L, Zhang R, Zhou J. JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling. Theranostics 2020; 10(18):8036-8050. doi:10.7150/thno.45843. Available from http://www.thno.org/v10p8036.htm

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Abstract

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. 18F-labeled JP1 (18F-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.

Keywords: melanoma, therapeutic peptide, NEDD4L, SP1, integrin αvβ3.