Macrolide analog F806 suppresses esophageal squamous cell carcinoma (ESCC) by blocking β1 integrin activation
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Li-Yan Li1,2,*, Hong Jiang3,*, Yang-Min Xie4, Lian-Di Liao1,2, Hui-Hui Cao1,2, Xiu-E Xu1,2, Bo Chen1,2, Fa-Min Zeng1,5, Ying-Li Zhang1,2, Ze-Peng Du1,2, Hong Chen3, Wei Huang3, Wei Jia3, Wei Zheng3, Jian-Jun Xie1,5, En-Min Li1,5, Li-Yan Xu1,2
1The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, P.R. China
2Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, P.R. China
3Fujian Key Laboratory of Screening for Novel Microbial Products, Fujian Institute of Microbiology, Fuzhou, Fujian, P.R. China
4Experimental Animal Center, Shantou University Medical College, Shantou, Guangdong, P.R. China
5Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, Guangdong, P.R. China
*These authors have contributed equally to this work
Li-Yan Xu, e-mail: email@example.com
En-Min Li, e-mail: firstname.lastname@example.org
Keywords: macrolide analog F806, β1 integrin, cell adhesion, anoikis, esophageal squamous cell carcinoma cells
Received: January 21, 2015 Accepted: March 14, 2015 Published: April 03, 2015
The paucity of new drugs for the treatment of esophageal squamous cell carcinoma (ESCC) limits the treatment options. This study characterized the therapeutic efficacy and action mechanism of a novel natural macrolide compound F806 in human ESCC xenograft models and cell lines. F806 inhibited growth of ESCC, most importantly, it displayed fewer undesirable side effects on normal tissues in two human ESCC xenograft models. F806 inhibited proliferation of six ESCC cells lines, with the half maximal inhibitory concentration (IC50) ranging from 9.31 to 16.43 μM. Furthermore, F806 induced apoptosis of ESCC cells, contributing to its growth-inhibitory effect. Also, F806 inhibited cell adhesion resulting in anoikis. Mechanistic studies revealed that F806 inhibited the activation of β1 integrin in part by binding to a novel site Arg610 of β1 integrin, suppressed focal adhesion formation, decreased cell adhesion to extracellular matrix and eventually triggered apoptosis. We concluded that F806 would potentially be a well-tolerated anticancer drug by targeting β1 integrin, resulting in anoikis in ESCC cells.
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