Opposite Regulation of CHOP and GRP78 and Synergistic Apoptosis Induction by Selenium Yeast and Fish Oil via AMPK Activation in Lung Adenocarcinoma Cells.

Ruey-Ho Kao,Simon Hsia,Jacqueline Whang-Peng,Gi-Ming Lai,I-Chun Lai,Wei-Lun Tsai,Hsin-Lun Lee,Jyh-Ming Chow,Yu-Mei Zheng,Chih-Jung Yao,Shuang-En Chuang,Chien-Huang Liao

doi:10.3390/nu10101458

Abstract

Selenium has been intensively studied for the use of cancer prevention and treatment. However, the clinical effects are still plausible. To enhance its efficacy, a combinational study of selenium yeast (SY) and fish oil (FO) was performed in A549, CL1-0, H1299, HCC827 lung adenocarcinoma (LADC) cells to investigate the enhancement in apoptosis induction and underlying mechanism. By sulforhodamine B staining, Western blot and flow cytometric assays, we found a synergism between SY and FO in growth inhibition and apoptosis induction of LADC cells. In contrast, the fetal lung fibroblast cells (MRC-5) were unsusceptible to this combination effect. FO synergized SY-induced apoptosis of A549 cells, accompanied with synergistic activation of AMP-activated protein kinase (AMPK) and reduction of Cyclooxygenase (COX)-2 and β-catenin. Particularly, combining with FO not only enhanced the SY-elevated proapoptotic endoplasmic reticulum (ER) stress marker CCAAT/enhancer-binding protein homologous protein (CHOP), but also reduced the cytoprotective glucose regulated protein of molecular weight 78 kDa (GRP78). Consequently, the CHOP downstream targets such as phospho-JNK and death receptor 5 were also elevated, along with the cleavage of caspase-8, -3, and the ER stress-related caspase-4. Accordingly, inhibition of AMPK by compound C diminished the synergistic apoptosis induction, and elevated CHOP/GRP78 ratio by SY combined with FO. The AMPK-dependent synergism suggests the combination of SY and FO for chemoprevention and integrative treatment of LADC.

Highlights

Lung cancer is the leading cause of cancer-related mortality worldwide, and its rate of incidence continues increasing [1]
It had been reported that 500 ng/mL was the upper limit of the mean plasma selenium levels associated with toxicity in human [28]
As apoptosis induction through endoplasmic reticulum (ER) stress cascade is crucial for the anticancer activity of selenium [8,15], dietary nutraceutical with complementary mechanism of action in modulating the cascade is engaging for this purpose

Summary

Introduction

Lung cancer is the leading cause of cancer-related mortality worldwide, and its rate of incidence continues increasing [1]. Selenium compounds have been intensively studied, in many experimental models, against several malignancies, including lung cancer [3]. A variety of clinical trials were conducted to evaluate the safety and efficacy of selenium in lung cancers patients [5,6]. A recent study of meta-analysis and meta-regression concluded that high selenium exposure decreased the risk of lung cancer, as well as other four types of cancers (breast, esophageal, gastric and prostate) [6], some outcomes of other trials were not as favorable as expected or even conflict [5,7]. As the potency of a single dietary component might be limited, further combinational study was prompted to enhance the efficacy of selenium for the prevention and treatment of lung cancer

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Conclusion