Dataset Information

Macrolide analog F806 suppresses esophageal squamous cell carcinoma (ESCC) by blocking ?1 integrin activation.

ABSTRACT: 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 ?M. 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 ?1 integrin in part by binding to a novel site Arg610 of ?1 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 ?1 integrin, resulting in anoikis in ESCC cells.

SUBMITTER: Li LY

PROVIDER: S-EPMC4599248 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other

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Macrolide analog F806 suppresses esophageal squamous cell carcinoma (ESCC) by blocking β1 integrin activation.

Li Li-Yan LY Jiang Hong H Xie Yang-Min YM Liao Lian-Di LD Cao Hui-Hui HH Xu Xiu-E XE Chen Bo B Zeng Fa-Min FM Zhang Ying-Li YL Du Ze-Peng ZP Chen Hong H Huang Wei W Jia Wei W Zheng Wei W Xie Jian-Jun JJ Li En-Min EM Xu Li-Yan LY

Oncotarget 20150601 18

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 maxima ...[more]

PMID: 25909284

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Project description:Esophageal squamous cell carcinoma (ESCC) is a deadly squamous cell carcinoma (SCC) of the esophagus. Development of SCCs is associated with the deregulation of the squamous cell lineage program and/or keratinocyte terminal differentiation by genomic and genetic aberrations; thus, these processes must be tightly controlled to maintain normal squamous cell development. Zinc finger protein 750 (ZNF750) is a gene involved in keratinocyte terminal differentiation and is frequently mutated and putatively silenced in ESCC, which implicates its function as a potential differentiation-related suppressor of ESCC. The present study aimed to elucidate the relationship between ZNF750 function to induce keratinocyte differentiation and tumor suppression in ESCC. The results demonstrated that chemical manipulation of esophageal keratinocyte differentiation in mouse normal esophageal epithelial organoids (mNEEO) implicated the involvement of the mouse homologue of ZNF750, Zfp750, in keratinocyte differentiation in premalignant cells. Bioinformatics analyses of data from high ZNF750-expressing ESCC tumors obtained from public databases and ZNF750-overexpressing ESCC cells compared with low ZNF750-expressing ESCC tumors and GFP-expressing ESCC cells, respectively, revealed enrichment of keratinocyte differentiation-related gene sets in these samples. Finally, the induction through to terminal differentiation of the keratinocyte by all-trans retinoic acid on parental ESCC cell lines led to the upregulation of the terminal differentiation marker Involucrin and a decrease in cell viability similar to that observed in ZNF750-overexpressing ESCC cells. The results of the present study demonstrated a functional link between the ability of ZNF750 to induce cell differentiation through to terminal differentiation and its function as a growth suppressor in ESCC. This study provides improved understanding of the role of ZNF750, a frequently mutated differentiation-related gene in ESCC, and its effects in ESCC pathogenesis.

Dataset Information

Macrolide analog F806 suppresses esophageal squamous cell carcinoma (ESCC) by blocking ?1 integrin activation.

Publications

Macrolide analog F806 suppresses esophageal squamous cell carcinoma (ESCC) by blocking β1 integrin activation.

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