Arsenic trioxide attenuates STAT-3 activity and epithelial-mesenchymal transition through induction of SHP-1 in gastric cancer cells

Sung Ho Kim, Hyo Soon Yoo, Moon Kyung Joo, Taehyun Kim, Jong Jae Park, Beom Jae Lee, Hoon Jai Chun, Sang Woo Lee, Young Tae Bak

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    15 Citations (Scopus)

    Abstract

    Background: We investigated the effect of arsenic trioxide (ATO) for inhibition of signal transducer and activator of transcription 3 (STAT3) and epithelial-mesenchymal transition (EMT) in gastric cancer cells, and the role of SH2 domain-containing phosphatase-1 (SHP-1) during this process. Methods: We used AGS cells, which showed minimal SHP-1 expression and constitutive STAT3 expression. After treatment of ATO, cellular migration and invasion were assessed by using wound closure assay, Matrigel invasion assay and 3-D culture invasion assay. To validate the role of SHP-1, pervanadate, a pharmacologic phosphatase inhibitor, and SHP-1 siRNA were used. Xenograft tumors were produced, and ATO or pervanadate were administered via intraperitoneal (IP) route. Results: Treatment of ATO 5 and 10 μM significantly decreased cellular migration and invasion in a dose-dependent manner. Western blot showed that ATO upregulated SHP-1 expression and downregulated STAT3 expression, and immunofluorescence showed upregulation with E-cadherin (epithelial marker) and downregulation of Snail1 (mesenchymal marker) expression by ATO treatment. Anti-migration and invasion effect and modulation of SHP-1/STAT3 axis by ATO were attenuated by pervanadate or SHP-1 siRNA. IP injection of ATO significantly decreased the xenograft tumor volume and upregulated SHP-1 expression, which were attenuated by co-IP injection of pervanadate. Conclusion: Our data suggest that ATO inhibits STAT3 activity and EMT process by upregulation of SHP-1 in gastric cancer cells.

    Original languageEnglish
    Article number150
    JournalBMC Cancer
    Volume18
    Issue number1
    DOIs
    Publication statusPublished - 2018 Feb 6

    Keywords

    • Arsenic trioxide
    • Epithelial-mesenchymal transition
    • SH2-containing protein tyrosine phosphatase 1
    • Signal transducer and activator of transcription 3

    ASJC Scopus subject areas

    • Oncology
    • Genetics
    • Cancer Research

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