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

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. 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.

Phosphorylation inhibition of protein-tyrosine phosphatase 1B tyrosine-152 induces bone regeneration coupled with angiogenesis for bone tissue engineering

“…CXCl12/CXCR4 can directly activate the integrin αvβ3 signaling pathway and then promote cell migration [ 45 ]. Activation of integrin αvβ3 is associated with invasion and metastasis of multiple tumors [ 46 ]. However, the recruitment of MSCs in the bone defect microenvironment has not been reported.…”

NEDD4L-induced ubiquitination mediating UBE2T degradation inhibits progression of lung adenocarcinoma via PI3K-AKT signaling

“…Our conclusion is supported by the following lines of evidence: (1) NEDD4L binds to UBE2T under the physiological conditions; (2) Cellular levels of UBE2T can be decreased or increased by NEDD4L overexpression or depletion, respectively; (3) The half-life of UBE2T protein is shortened or extended by NEDD4L overexpression or depletion, respectively; (4) NEDD4L leads to UBE2T ubiquitylation. NEDD4L has been shown bind to and ubiquitylate many cellular proteins for targeted degradation [ 35 , 36 ], but has never about it targets UBE2T. Taken together, we first report that UBE2T is a novel physiological substrate of the E3 ubiquitin ligase NEDD4L.…”

“…Emerging evidences have reported that NEDD4L may function as a tumor suppressor that is frequently reduced in human carcinomas of pancreatic [ 37 ], colorectal [ 35 ], melanoma [ 36 ], ovarian [ 38 ] and lung [ 25 , 26 ]. But some studies reported that NEDD4L promoted lung cancer cell survival [ 27 ].…”

ALCAP2 inhibits lung adenocarcinoma cell proliferation, migration and invasion via the ubiquitination of β-catenin by upregulating the E3 ligase NEDD4L

“…Neural precursor cell expresses developmentally downregulated 4-like (NEDD4L), a member of the NEDD4 family that contains a HECT domain for Ub protein ligation [ 23 ]. NEDD4L has been reported to be downregulated in multiple types of cancers and acts as a tumour suppressor gene in melanoma [ 24 ], colorectal cancer [ 25 ], lung cancer [ 26 ], and other cancers.…”