Ellagic acid promotes apoptosis of human cervical cancer cells through endoplasmic reticulum stress and mitochondrial damage / 中国药理学通报

Aim To investigate the effect of ellagic acid on human cervical cancer cells and its correlation with endoplasmic reticulum stress ( ERS) - mitochondrial apoptosis pathway. Methods Hela cells were treated with ellagic acid, and cell survival rate, apoptosis and expression of ERS mitochondrial apoptosis pathway protein were detected. After pretreatment with ERS inhibitor 4-PBA, the expression of mitochondrial apoptosis pathway protein was detected. Results Ellagic acid showed concentration-dependent and time- dependent killing effect on Hela cells, and could significantly increase the apoptosis of Hela cells. Ellagic acid significantly increased the expression levels of ERS related proteins (GRP78, CHOP, p-PERK, p-IREl) in Hela cells, and significantly increased the expression levels of mitochondrial proapoptotic proteins . Bax and cleaved caspase-3, while significantly decreased the expression level of mitochondrial anti apop- totic protein Bcl-2. Another group of experiments showed that pretreatment with ERS inhibitor 4-PBA could significantly reduce the expression levels of Bax and cleaved caspase-3, and significantly increase the expression level of Bcl-2, which was close to the normal group. Conclusions Ellagic acid can significantly promote the apoptosis of human cervical cancer cells, and its mechanism is related to ERS mitochondrial apoptosis pathway.

4-phenylbutyric Acid Regulates Collagen Synthesis and Secretion Induced by High Concentrations of Glucose in Human Gingival Fibroblasts

High glucose leads to physio/pathological alterations in diabetes patients. We investigated collagen production in human gingival cells that were cultured in high concentrations of glucose. Collagen synthesis and secretion were increased when the cells were exposed to high concentrations of glucose. We examined endoplasmic reticulum (ER) stress response because glucose metabolism is related to ER functional status. An ER stress response including the expression of glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), inositol requiring enzyme alpha (IRE-1alpha) and phosphoreukaryotic initiation factor alpha (p-eIF-2alpha) was activated in the presence of high glucose. Activating transcription factor 4 (ATF-4), a downstream protein of p-eIF-2alpha as well as a transcription factor for collagen, was also phosphorylated and translocalized into the nucleus. The chemical chaperone 4-PBA inhibited the ER stress response and ATF-4 phosphorylation as well as nuclear translocation. Our results suggest that high concentrations of glucose-induced collagen are linked to ER stress and the associated phosphorylation and nuclear translocation of ATF-4.