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G-Protein-Coupled Receptor 120 Mediates DHA-Induced Apoptosis by Regulating IP3R, ROS and, ER Stress Levels in Cisplatin-Resistant Cancer Cells

  • Shin, Jong-Il (Department of Biological Sciences, Konkuk University) ;
  • Jeon, Yong-Joon (Department of Biological Sciences, Konkuk University) ;
  • Lee, Sol (Department of Biological Sciences, Konkuk University) ;
  • Lee, Yoon Gyeong (Department of Biological Sciences, Konkuk University) ;
  • Kim, Ji Beom (Department of Biological Sciences, Konkuk University) ;
  • Lee, Kyungho (Department of Biological Sciences, Konkuk University)
  • Received : 2018.11.27
  • Accepted : 2018.12.24
  • Published : 2019.03.31

Abstract

The omega-3 fatty acid docosahexaenoic acid (DHA) is known to induce apoptosis and cell cycle arrest via the induction of reactive oxygen species (ROS) production and endoplasmic reticulum (ER) stress in many types of cancers. However, the roles of DHA in drug-resistant cancer cells have not been elucidated. In this study, we investigated the effects of DHA in cisplatin-resistant gastric cancer SNU-601/cis2 cells. DHA was found to induce ROS-dependent apoptosis in these cells. The inositol 1,4,5-triphosphate receptor ($IP_3R$) blocker 2-aminoethyl diphenylboninate (2-APB) reduced DHA-induced ROS production, consequently reducing apoptosis. We also found that G-protein-coupled receptor 120 (GPR120), a receptor of long-chain fatty acids, is expressed in SNU-601/cis2 cells, and the knockdown of GPR120 using specific shRNAs alleviated DHA-mediated ROS production and apoptosis. GPR120 knockdown reduced the expression of ER stress response genes, similar to the case for the pre-treatment of the cells with N-acetyl-L-cysteine (NAC), an ROS scavenger, or 2-APB. Indeed, the knockdown of C/EBP homologous protein (CHOP), a transcription factor that functions under ER stress conditions, markedly reduced DHA-mediated apoptosis, indicating that CHOP plays an essential role in the anti-cancer activity of DHA. These results suggest that GPR120 mediates DHA-induced apoptosis by regulating $IP_3R$, ROS, and ER stress levels in cisplatin-resistant cancer cells, and that GPR120 is an effective chemotherapeutic target for cisplatin resistance.

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Fig. 1. DHA treatment induces apoptosis in cisplatin-resistant gastric cancer cells.

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Fig. 2. DHA treatment induces ROSdependent apoptosis through IP3R activation in SNU-601/cis2 cells.

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Fig. 3. Downregulation of GPR120 diminishes DHA-mediated apoptosis in SNU-601/cis2 cells.

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Fig. 4. DHA-induced CHOP expression is involved with GPR120, IP3R, and ROS in SNU-601/cis2 cells.

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Fig. 5. CHOP is involved in DHA-mediated apoptosis in SNU-601/cis2 cells.

Acknowledgement

Supported by : Konkuk University

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