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J Agric Food Chem. 2017 Dec 27;65(51):11179-11191. doi: 10.1021/acs.jafc.7b02358. Epub 2017 Dec 15.

Pterostilbene Enhances TRAIL-Induced Apoptosis through the Induction of Death Receptors and Downregulation of Cell Survival Proteins in TRAIL-Resistance Triple Negative Breast Cancer Cells.

Hung CM1,2, Liu LC3,4, Ho CT5, Lin YC6,7,8, Way TD9,10.

Author information

1
Department of General Surgery, E-Da Hospital, I-Shou University , Kaohsiung, Taiwan.
2
School of Medicine, I-Shou University , Kaohsiung, Taiwan.
3
Department of Surgery, China Medical University Hospital , Taichung, Taiwan.
4
School of Medicine, College of Medicine, China Medical University , Taichung, Taiwan.
5
Department of Food Science, Rutgers University , New Brunswick, New Jersey 08901, United States.
6
Division of Neurosurgery, Buddhist Tzu Chi General Hospital, Taichung Branch , Taichung, Taiwan.
7
School of Medicine, Tzu Chi University , Hualien, Taiwan.
8
Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology , Taichung, Taiwan.
9
Department of Biological Science and Technology, College of Biopharmaceutical and Food Sciences, China Medical University , Taichung, Taiwan.
10
Department of Health and Nutrition Biotechnology, Asia University , Taichung, Taiwan.

Abstract

Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is nontoxic to normal cells and preferentially cytotoxic to cancer cells. Recent data suggest that malignant breast cancer cells often become resistant to TRAIL. Pterostilbene (PTER), a naturally occurring analogue of resveratrol found in blueberries, is known to induce cancer cells to undergo apoptosis. In the present study, we examined whether PTER affects TRAIL-induced apoptosis and its mechanism in TRAIL-resistant triple negative breast cancer (TNBC) cells. Our data indicated that PTER induced apoptosis (14.68 ± 3.78% for 40 μM PTER vs 1.98 ± 0.25% for control, p < 0.01) in TNBC cells and enhanced TRAIL-induced apoptosis in TRAIL-resistant TNBC cells (18.45 ± 4.65% for 40 μM PTER vs 29.38 ± 6.35% for combination of 40 μM PTER and 100 ng/mL TRAIL, p < 0.01). We demonstrated that PTER induced death receptors DR5 and DR4 as well as decreased decoy receptor DcR-1 and DcR-2 expression. PTER also decreased the antiapoptotic proteins c-FLIPS/L, Bcl-Xl, Bcl-2, survivin, and XIAP. PTER induced the cleavage of bid protein and caused proapoptotic Bax accumulation. Moreover, we found that PTER induced the expression of DR4 and DR5 through the reactive oxygen species (ROS)/ endoplasmic reticulum (ER) stress/ERK 1/2 and p38/C/EBP-homologous protein (CHOP) signaling pathways. Overall, our results showed that PTER potentiated TRAIL-induced apoptosis via ROS-mediated CHOP activation leading to the expression of DR4 and DR5.

KEYWORDS:

ROS; TRAIL; death receptor; pterostilbene; triple negative breast cancer

PMID:
29164887
DOI:
10.1021/acs.jafc.7b02358
[Indexed for MEDLINE]

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