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

doi:10.1016/j.biocel.2017.06.010

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 journal › Article › peer-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 language	English
Pages (from-to)	147-156
Number of pages	10
Journal	International Journal of Biochemistry and Cell Biology
Volume	89
DOIs	https://doi.org/10.1016/j.biocel.2017.06.010
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.biocel.2017.06.010

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Na, Y. J., Lee, D. H., Kim, J. L., Kim, B. R., Park, S. H., Jo, M. J., Jeong, S., Kim, H. J., Lee, S. Y., Jeong, Y. A., & Oh, S. C. (2017). Cyclopamine sensitizes TRAIL-resistant gastric cancer cells to TRAIL-induced apoptosis via endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation. International Journal of Biochemistry and Cell Biology, 89, 147-156. https://doi.org/10.1016/j.biocel.2017.06.010

Cyclopamine sensitizes TRAIL-resistant gastric cancer cells to TRAIL-induced apoptosis via endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation. / Na, Yoo Jin; Lee, Dae Hee; Kim, Jung Lim et al.
In: International Journal of Biochemistry and Cell Biology, Vol. 89, 08.2017, p. 147-156.

Research output: Contribution to journal › Article › peer-review

Na, YJ, Lee, DH, Kim, JL, Kim, BR, Park, SH, Jo, MJ, Jeong, S, Kim, HJ, Lee, SY, Jeong, YA & Oh, SC 2017, 'Cyclopamine sensitizes TRAIL-resistant gastric cancer cells to TRAIL-induced apoptosis via endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation', International Journal of Biochemistry and Cell Biology, vol. 89, pp. 147-156. https://doi.org/10.1016/j.biocel.2017.06.010

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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.",

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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: {\textcopyright} 2017",

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AU - Na, Yoo Jin

AU - Lee, Dae Hee

AU - Kim, Jung Lim

AU - Kim, Bo Ram

AU - Park, Seong Hye

AU - Jo, Min Jee

AU - Jeong, Soyeon

AU - Kim, Hong Jun

AU - Lee, Suk young

AU - Jeong, Yoon A.

AU - Oh, Sang Cheul

N1 - 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

PY - 2017/8

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N2 - 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.

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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