当前位置： SCI文献检索 > JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH期刊下所有文献 > (Arg)9-SH2 superbinder: a novel promising anticancer therapy to melanoma by blocking phosphotyrosine signaling.

(Arg)9-SH2 superbinder: a novel promising anticancer therapy to melanoma by blocking phosphotyrosine signaling.

Abstract：

BACKGROUND:Melanoma is a malignant tumor with high misdiagnosis rate and poor prognosis. The bio-targeted therapy is a prevailing method in the treatment of melanoma; however, the accompanying drug resistance is inevitable. SH2 superbinder, a triple-mutant of the Src Homology 2 (SH2) domain, shows potent antitumor ability by replacing natural SH2-containing proteins and blocking multiple pY-based signaling pathways. Polyarginine (Arg)9, a powerful vector for intracellular delivery of large molecules, could transport therapeutic agents across cell membrane. The purpose of this study is to construct (Arg)9-SH2 superbinder and investigate its effects on melanoma cells, expecting to provide potential new approaches for anti-cancer therapy and overcoming the unavoidable drug resistance of single-targeted antitumor agents. METHODS:(Arg)9 and SH2 superbinder were fused to form (Arg)9-SH2 superbinder via genetic engineering. Pull down assay was performed to identify that (Arg)9-SH2 superbinder could capture a wide variety of pY proteins. Immunofluorescence was used to detect the efficiency of (Arg)9-SH2 superbinder entering cells. The proliferation ability was assessed by MTT and colony formation assay. In addition, wound healing and transwell assay were performed to evaluate migration of B16F10, A375 and A375/DDP cells. Moreover, apoptosis caused by (Arg)9-SH2 superbinder was analyzed by flow cytometry-based Annexin V/PI. Furthermore, western blot revealed that (Arg)9-SH2 superbinder influenced some pY-related signaling pathways. Finally, B16F10 xenograft model was established to confirm whether (Arg)9-SH2 superbinder could restrain the growth of tumor. RESULTS:Our data showed that (Arg)9-SH2 superbinder had the ability to enter melanoma cells effectively and displayed strong affinities for various pY proteins. Furthermore, (Arg)9-SH2 superbinder could repress proliferation, migration and induce apoptosis of melanoma cells by regulating PI3K/AKT, MAPK/ERK and JAK/STAT signaling pathways. Importantly, (Arg)9-SH2 superbinder could significantly inhibit the growth of tumor in mice. CONCLUSIONS:(Arg)9-SH2 superbinder exhibited high affinities for pY proteins, which showed effective anticancer ability by replacing SH2-containing proteins and blocking diverse pY-based pathways. The remarkable ability of (Arg)9-SH2 superbinder to inhibit cancer cell proliferation and tumor growth might open the door to explore the SH2 superbinder as a therapeutic agent for cancer treatment.

journal_name

J Exp Clin Cancer Res

journal_title

Journal of experimental & clinical cancer research : CR

authors

Liu AD,Xu H,Gao YN,Luo DN,Li ZF,Voss C,Li SSC,Cao X

doi

10.1186/s13046-018-0812-5

subject

Has Abstract

pub_date

2018-07-05 00:00:00

pages

138

issue

eissn

0392-9078

issn

1756-9966

pii

10.1186/s13046-018-0812-5

journal_volume

pub_type

杂志文章

在线工具

(Arg)9-SH2 superbinder: a novel promising anticancer therapy to melanoma by blocking phosphotyrosine signaling.