ATPR‐induced G₀/G₁ phase arrest in gastric cancer cells by regulating the binding of 14‐3‐3ε and filamin A

Abstract

Abstract4‐amino‐2‐trifluoromethyl‐phenyl retinate (ATPR) was able to induce the G0/G1 phase arrest in gastric cancer SGC‐7901 cells by downregulating 14‐3‐3ε. However, the mechanisms underlying this effect have not been fully elucidated. Because 14‐3‐3ε functions as a molecular chaperone on cell cycle regulation, the interaction between 14‐3‐3ε and the target proteins is worth an in‐depth study. In this study, the use of targeting proteomics identified 352 14‐3‐3ε‐binding proteins in SGC‐7901 cells. Analysis of gene ontology (GO) was performed using PANTHER to annotate the biological processes, protein classes, and pathways of these proteins. In 25 cell cycle‐related proteins, filamin A was reduced following ATPR treatment, and this change was validated by immunoprecipitation. The cell cycle was arrested at the G0/G1 phase following ATPR treatment or filamin A silencing in SGC‐7901 cells. Furthermore, subcellular expression analysis showed that 14‐3‐3ε and filamin A were transferred from the cytoplasm to the nucleus after ATPR treatment. On the other hand, overexpression of 14‐3‐3ε, in SGC‐7901 cells, resulted in an increase in the total cellular level of filamin A and an increase in the subcellular localization of filamin A in the cytoplasm. ATPR treatment of the 14‐3‐3ε overexpression cells decreased the total level of filamin A and redistributed filamin A protein from the cytoplasm to the nucleus. Immunohistochemical analysis showed that the expression levels of 14‐3‐3ε and filamin A in gastric cancer tissues were significantly higher, with a predominant localization in the cytoplasm, compared to the levels in matched tissues. Taken together, our results suggest that ATPR can induce nuclear localization of filamin A by reducing the binding of 14‐3‐3ε and filamin A, which may be the mechanism of ATPR‐induced G0/G1 phase arrest.

Integrative Role of 14-3-3ε in Sleep Regulation

“…14-3-3 proteins are found to be important in both cancer- and age-related neurodegenerative disease [ 40 ], which can directly interact with yki [ 17 ], an important cancer factor in the Hippo pathway [ 19 , 40 ]. Previous studies indicated that 14-3-3ε is involved in gastric cancer and colorectal cancer [ 41 , 42 , 43 , 44 , 45 , 46 ], and disrupted sleep is a risk factor that contributes to cancer [ 47 ]. Many current papers showed a link between molecules upregulated in cancer patients and selected sleep disturbances.…”

“…In this current study, we found that 14-3-3ε, controlled by Clock, regulates sleep through pathways of both the 14-3-3ε/Ubx/PDF and neurotransmitters. In addition, there are previous reports that 14-3-3ε is also related to cancers [ 40 , 41 , 42 , 43 , 44 , 45 , 46 ], indicating that 14-3-3ε is a multifunctional gene in Drosophila regulating different physiological activities. Currently, the direct relationship between cancer and sleep is still unclear, which need to be carefully designed for systematical investigation in future.…”