Apoptotic effect of fluoxetine through the endoplasmic reticulum stress pathway in the human gastric cancer cell line AGS.
Phyu Phyu KhinWah Wah PoWynn TheinUy Dong SohnPublished in: Naunyn-Schmiedeberg's archives of pharmacology (2019)
Gastric cancer is the fourth most common cancer in the world. Fluoxetine (FLX), a selective serotonin reuptake inhibitor, can inhibit the growth of cancer cells by inducing apoptotic cell death through various signaling pathways. This study was aimed to determine the mechanism of apoptotic cell death induced by FLX in AGS cells. MTT assay for cell viability test and colony forming assay was performed for detection of cell proliferation. Western blot analysis was conducted for protein expression. Increased fluorescence intensity and chromatin condensation were observed using DAPI staining. Production of reactive oxygen species (ROS) was measured by DCFDA assay. AGS cell proliferation was remarkedly inhibited by FLX in a dose-dependent manner starting at a concentration of 20 μM. The expression of death receptors was increased, which resulted in elevated expression of activated caspases and cleaved PARP, leading to FLX-induced apoptosis. Moreover, FLX significantly increased production of ROS, and N-acetyl cysteine, which scavenges ROS, attenuated the cytotoxic effects of FLX. In addition, treatment with FLX increased the expression of the endoplasmic reticulum (ER) stress marker, CHOP. P53 protein expression in AGS cells also decreased significantly with FLX treatment. Inhibition of ER stress significantly decreased the expressions of death receptor 5 (DR5), cleaved caspase 3, and cleaved PARP, but not to control levels. FLX-induced apoptosis in AGS involved upregulation of death receptors, ROS generation, and activation of ER stress.
Keyphrases
- induced apoptosis
- cell death
- endoplasmic reticulum stress
- signaling pathway
- cell cycle arrest
- cell proliferation
- poor prognosis
- oxidative stress
- dna damage
- reactive oxygen species
- pi k akt
- binding protein
- endothelial cells
- gene expression
- squamous cell carcinoma
- long non coding rna
- combination therapy
- young adults
- genome wide
- diffuse large b cell lymphoma
- single molecule
- south africa
- fluorescent probe
- replacement therapy
- flow cytometry
- sensitive detection
- papillary thyroid
- living cells