Original articles
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. PEP06 polypeptide 30 is a novel cluster-dissociating agent inhibiting αv integrin/FAK/Src signaling in oral squamous cell carcinoma cells[J]. Acta Pharmaceutica Sinica B, 2019, 9(6): 1163-1173

PEP06 polypeptide 30 is a novel cluster-dissociating agent inhibiting αv integrin/FAK/Src signaling in oral squamous cell carcinoma cells
Gulnara Tuguzbaevaa,c,d,e, Er Yueb, Xi Chenb, Lina Hed, Xinlei Lic, Jiaming Juc, Ying Qinc, Valentin Pavlova, Yanjie Lub,c, Wenting Jiab,c, Yunlong Baib,c, Yumei Niud, Baofeng Yangb,c
a Central Laboratory of Scientific Research, Bashkir State Medical University, Ufa 450008, Russian Federation;
b 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;
c Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China;
d Department of Endodontics, the First Affiliated Hospital of Harbin Medical University, Harbin 150081, China;
e Department of Orthopedic Dentistry and Maxillofacial Surgery, Bashkir State Medical University, Ufa 450008, Russian Federation
Collectively migrating tumor cells have been recently implicated in enhanced metastasis of epithelial malignancies. In oral squamous cell carcinoma (OSCC), αv 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 cluster-dissociating therapeutic agent in vitro. Firstly, we found marked enrichment of αv integrin in collectively invading multicellular clusters in human OSCCs. Our study revealed that metastatic progression of OSCC was associated with augmented immunostaining of αv integrin in cancerous lesions. Following PEP06 treatment, cell clustering on fibronectin, migration, multicellular aggregation, anchorage-independent survival and colony formation of OSCC were significantly inhibited. Moreover, PEP06 suppressed αv integrin/FAK/Src 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 αv 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.
Key words:    Oral squamous cell carcinoma    Tumor cell clusters    Collective migration    Metastasis    αv integrin/FAK/RC   
Received: 2019-07-01     Revised: 2019-10-09
DOI: 10.1016/j.apsb.2019.10.005
Funds: The authors thank Dr. Shuyuan Guo and Dr. Shamil Khusnutdinov for their technical support in immunohistochemical analysis of OSCC clinical samples and also Prof. Yong Zhang for his administrative support. This work was funded by the National Natural Science Foundation of China (grant Nos. 81730012 and 81673426); and the Grant of Republic Bashkortostan for Young Scientists (grant No. 26 GR).
Corresponding author: Yumei Niu, Baofeng Yang     Email:yumeiniu@163.com;yangbf@ems.hrbmu.edu.cn
Author description:
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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

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