PEP06 polypeptide 30 is a novel clusterdissociating agent inhibiting αv integrin/FAK/Src signaling in oral squamous cell carcinoma cells  

作　　者：Gulnara Tuguzbaeva Er Yue Xi Chen Lina He Xinlei Li Jiaming Ju Ying Qin Valentin Pavlov Yanjie Lu Wenting Jia Yunlong Bai Yumei Niu Baofeng Yang 

机构地区：[1]Central Laboratory of Scientific Research,Bashkir State Medical University,Ufa 450008,Russian Federation [2]Department of Pharmacology(State-Province Key Laboratories of BiomedicineePharmaceutics of China,Key Laboratory of Cardiovascular Research,Ministry of Education),College of Pharmacy,Harbin Medical University,Harbin 150081,China [3]Translational Medicine Research and Cooperation Center of Northern China,Heilongjiang Academy of Medical Sciences,Harbin 150081,China [4]Department of Endodontics,the First Affiliated Hospital of Harbin Medical University,Harbin 150081,China [5]Department of Orthopedic Dentistry and Maxillofacial Surgery,Bashkir State Medical University,Ufa 450008,Russian Federation

出　　处：《Acta Pharmaceutica Sinica B》2019年第6期1163-1173,共11页药学学报（英文版）

基　　金：funded by the National Natural Science Foundation of China(grant Nos.81730012 and 81673426);the Grant of Republic Bashkortostan for Young Scientists(grant No.26 GR).

摘　　要：Collectively migrating tumor cells have been recently implicated in enhanced metastasis of epithelial malignancies.In oral squamous cell carcinoma(OSCC),av integrin is a crucial mediator of multicellular clustering and collective movement in vitro;however,its contribution to metastatic spread remains to be addressed.According to the emerging therapeutic concept,dissociation of tumor clusters into single cells could significantly suppress metastasis-seeding ability of carcinomas.This study aimed to investigate the anti-OSCC potential of novel endostatin-derived polypeptide PEP06 as a clusterdissociating therapeutic agent in vitro.Firstly,we found marked enrichment ofαv integrin in collectivelyinvading multicellular clusters in human OSCCs.Our study revealed that metastatic progression of OSCC was associated with augmented immunostaining of av integrin in cancerous lesions.Following PEP06treatment,cell clustering on fibronectin,migration,multicellular aggregation,anchorage-independent survival and colony formation of OSCC were significantly inhibited.Moreover,PEP06 suppressed av integrin/FAK/Sre signaling in OSCC cells.PEP06-induced loss of active Src and E-cadherin from cell-cell contacts contributed to diminished collective migration of OSCC in vitro.Overall,these results suggest that PEP06 polypeptide 30 inhibiting av integrin/FAK/Src signaling and disrupting E-cadherin-based intercellular junctions possesses anti-metastatic potential in OSCC by acting as a cluster-dissociating therapeutic agent.Collectively migrating tumor cells have been recently implicated in enhanced metastasis of epithelial malignancies.In oral squamous cell carcinoma (OSCC),av integrin is a crucial mediator of multicellular clustering and collective movement in vitro;however,its contribution to metastatic spread remains to be addressed.According to the emerging therapeutic concept,dissociation of tumor clusters into single cells could significantly suppress metastasis-seeding ability of carcinomas.This study aimed to investigate the anti-OSCC potential of novel endostatin-derived polypeptide PEP06 as a clusterdissociating therapeutic agent in vitro.Firstly,we found marked enrichment ofαv integrin in collectivelyinvading multicellular clusters in human OSCCs.Our study revealed that metastatic progression of OSCC was associated with augmented immunostaining of av integrin in cancerous lesions.Following PEP06treatment,cell clustering on fibronectin,migration,multicellular aggregation,anchorage-independent survival and colony formation of OSCC were significantly inhibited.Moreover,PEP06 suppressed av integrin/FAK/Sre signaling in OSCC cells.PEP06-induced loss of active Src and E-cadherin from cell-cell contacts contributed to diminished collective migration of OSCC in vitro.Overall,these results suggest that PEP06 polypeptide 30 inhibiting av integrin/FAK/Src signaling and disrupting E-cadherin-based intercellular junctions possesses anti-metastatic potential in OSCC by acting as a cluster-dissociating therapeutic agent.

关 键 词：Oral squamous CELL carcinoma Tumor CELL clusters Collective migration Metastasis ΑV integrin/FAK/RC SIGNALING RGD 

分 类 号：R739.8[医药卫生—肿瘤]