Trichomonas vaginalis induces apoptosis via ROS and ER stress response through ER–mitochondria crosstalk in SiHa cells

Abstract

Background Trichomonas vaginalis causes lesions on the cervicovaginal mucosa in women; however, its pathogenesis remains unclear. We have investigated the involvement of the endoplasmic reticulum (ER) in the induction of apoptosis by T. vaginalis and its molecular mechanisms in human cervical cancer SiHa cells. Methods Apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), ER stress response and Bcl-2 family protein expression were evaluated using immunocytochemistry, flow cytometry, 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide dye staining and western blotting. Results Trichomonas vaginalis induced mitochondrial ROS production, apoptosis, the ER stress response and mitochondrial dysfunction, such as MMP depolarization and an imbalance in Bcl-2 family proteins, in SiHa cells in a parasite burden- and infection time-dependent manner. Pretreatment with N-acetyl cysteine (ROS scavenger) or 4-phenylbutyric acid (4-PBA; ER stress inhibitor) significantly alleviated apoptosis, mitochondrial ROS production, mitochondrial dysfunction and ER stress response in a dose-dependent manner. In addition, T. vaginalis induced the phosphorylation of apoptosis signal regulating kinase 1 (ASK1) and c-Jun N-terminal kinases (JNK) in SiHa cells, whereas 4-PBA or SP600125 (JNK inhibitor) pretreatment significantly attenuated ASK1/JNK phosphorylation, mitochondrial dysfunction, apoptosis and ER stress response in SiHa cells, in a dose-dependent manner. Furthermore, T. vaginalis excretory/secretory products also induced mitochondrial ROS production, apoptosis and the ER stress response in SiHa cells, in a time-dependent manner. Conclusions Trichomonas vaginalis induces apoptosis through mitochondrial ROS and ER stress responses, and also promotes ER stress-mediated mitochondrial apoptosis via the IRE1/ASK1/JNK/Bcl-2 family protein pathways in SiHa cells. These data suggest that T. vaginalis-induced apoptosis is affected by ROS and ER stress response via ER–mitochondria crosstalk. Graphical Abstract

Restoration and preservation effects of mung bean antioxidant peptides on H2O2‐induced WRL‐68 cells via Keap1‐Nrf2 pathway

“…are generated in the mitochondrial electron transport chain. These electron‐bearing products are involved in energy metabolism on the one hand, and generate oxidation products such as ROS, reactive nitrogen species, and lipid peroxides through a series of reactions on the other hand (Gao et al, 2021 ). The mitochondrial membrane potential controls the rate of ROS production by mitochondria, and when mitochondria are exposed to outside stimuli such as H 2 O 2 and hyperlipidemia, the production of reactive oxygen species in the body rises dramatically (Bravo‐Sagua et al, 2013 ).…”

Combination of TrxR1 inhibitor and lenvatinib triggers ROS-dependent cell death in human lung cancer cells

“…It has been shown that ROS accumulation can result in cell death by inducing ER stress 33 , 34 . Furthermore, ROS is a noteworthy activator of the JNK signaling pathway 30 , 50 .…”

“…Elevated ROS level has been proved to be interrelated to the activation of ER stress [33][34][35]. Therefore, we investigated whether LEN and AF can synergistically trigger ER stress.…”

Combination of Zearalenone and Deoxynivalenol Induces Apoptosis by Mitochondrial Pathway in Piglet Sertoli Cells: Role of Endoplasmic Reticulum Stress

“…The addition of Mdivi-1 inhibited the expression of the ERS markers GRP78 and C/EBP homologous protein, inhibited Caspase-3 activation, and the rate of apoptosis in hippocampal neurons [ 38 ]. In SiHa cells, Trichomonas vaginalis triggers ERS-induced mitochondrial apoptosis through the IRE1/ASK1/JNK/ Bcl-2 family protein pathways [ 39 ]. Our previous research indicates that adding 4-PBA can alleviate toxic damage and apoptosis in porcine germ cells and alleviate ERS caused by ZEA [ 14 , 40 ].…”