Cyclopamine sensitizes TRAIL-resistant gastric cancer cells to TRAIL-induced apoptosis via endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation

Yoo Jin Na, Dae Hee Lee, Jung Lim Kim, Bo Ram Kim, Seong Hye Park, Min Jee Jo, Soyeon Jeong, Hong Jun Kim, Suk young Lee, Yoon A. Jeong, Sang Cheul Oh

    Research output: Contribution to journalArticlepeer-review

    22 Citations (Scopus)

    Abstract

    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is one of the most effective cancer treatments owing to its ability to selectively kill cancer cells, without affecting normal cells. However, it has been reported that several gastric cancer cells show resistance to TRAIL because of a scarcity of death receptor 5 (DR5) expressed on the cell surface. In this study, we show that cyclopamine sensitizes gastric cancer cells to TRAIL-induced apoptosis by elevating the expression of DR5. Interestingly, survivin hampers the existence of DR5 protein under normal conditions and cyclopamine decreases the expression of survivin, thus acting as a TRAIL sensitizer. Mechanistically, cyclopamine induces endoplasmic reticulum (ER) stress via reactive oxygen species (ROS) and CHOP, the last protein of the ER stress pathway and it regulates the proteasome degradation of survivin. Taken together, our results indicate that cyclopamine can be used for combination therapy in TRAIL-resistant gastric cancer cells.

    Original languageEnglish
    Pages (from-to)147-156
    Number of pages10
    JournalInternational Journal of Biochemistry and Cell Biology
    Volume89
    DOIs
    Publication statusPublished - 2017 Aug

    Bibliographical note

    Funding Information:
    This work was supported by the National Research Foundation (NRF) of Korea grant funded by the Korean government (MSIP) [NRF- 2015R1D1A1A01058303] and supported by Business for Cooperative R&D between Industry, Academy, and Research Institute funded Korea Small and Medium Business Administration in 20 [C0421445].

    Publisher Copyright:
    © 2017

    Keywords

    • CHOP
    • Cyclopamine
    • Death receptor 5
    • Survivin
    • TRAIL-resistance

    ASJC Scopus subject areas

    • Biochemistry
    • Cell Biology

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