Oncotarget

Research Papers:

Phytoagent deoxyelephantopin derivative inhibits triple negative breast cancer cell activity by inducing oxidative stress-mediated paraptosis-like cell death

Jeng-Yuan Shiau, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee and Lie-Fen Shyur _

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Oncotarget. 2017; 8:56942-56958. https://doi.org/10.18632/oncotarget.18183

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Abstract

Jeng-Yuan Shiau1,4, Kyoko Nakagawa-Goto2, Kuo-Hsiung Lee3 and Lie-Fen Shyur1,4,5

1Institute of Biotechnology, National Taiwan University, Taipei, Taiwan

2College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan

3Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA

4Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan

5PhD Program in Translational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

Correspondence to:

Lie-Fen Shyur, email: [email protected]

Keywords: breast cancer, sesquiterpene lactone, oxidative stress, paraptosis

Received: March 10, 2017     Accepted: April 18, 2017     Published: May 25, 2017

ABSTRACT

Triple negative breast cancer (TNBC) is a highly metastatic cancer among the breast cancer subgroups. A thorny issue for clinical therapy of TNBC is lack of an efficient targeted therapeutic strategy. We previously created a novel sesquiterpene lactone analog (named DETD-35) derived from plant deoxyelephantopin (DET) which exhibits potent effects against human TNBC MDA-MB-231 tumor growth in a xenograft mouse model. Here we studied the mechanisms of both DET and DETD-35 against MDA-MB-231 cells. DETD-35 (3-fold decreased in IC50) exhibited better anti-TNBC cell activity than DET as observed through induction of reactive oxygen species production (within 2 h treatment) and damage to the ER structures, resulting in ER-derived cytoplasmic vacuolation and ubiquitinated protein accumulation in the treated cells. Intriguingly, the effects of both compounds were blockaded by pretreatment with ROS scavengers, N-acetylcysteine and reduced glutathione, and protein synthesis inhibitor, cycloheximide. Further, knockdown of MEK upstream regulator RAF1 and autophagosomal marker LC3, and co-treatment with JNK or ERK1/2 inhibitor resulted in the most significant attenuation of DETD-35-induced morphological and molecular or biochemical changes in cancer cells, while the inhibitory effect of DET was not influenced by MAPK inhibitor treatment. Therefore, DETD-35 exerted both ER stress-mediated paraptosis and apoptosis, which may explain its superior activity to DET against TNBC cells. Although the chemotherapeutic drug paclitaxel induced vacuole-like structures in MDA-MB-231 cells, no paraptotic cell death features were detected. This study provides a strategy for combating TNBC through sesquiterpene lactone analogs by induction of oxidative and ER stresses that cause paraptosis-like cell death.


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