Abstract
BackgroundTrichomonas 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.MethodsApoptosis, 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.ResultsTrichomonas 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.ConclusionsTrichomonas 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
Highlights
Trichomonas vaginalis causes lesions on the cervicovaginal mucosa in women; its pathogen‐ esis remains unclear
Trichomonas vaginalis‐induced cytotoxicity and mitochondrial reactive oxygen species (ROS) production in SiHa cells in a parasite burden‐ and infection time‐dependent manner To determine the adequate multiplicity of infection (MOI) and infection time for induction of apoptosis and endoplasmic reticulum (ER) stress response in live T. vaginalis-infected SiHa cells, we performed the lactate dehydrogenase (LDH) assay and western blotting under various conditions
Our results showed that live T. vaginalis induced apoptosis through mitochondrial ROS and ER stress responses and promoted the ER stress response both directly and in an ROS-dependent manner in human cervical cancer SiHa cells, dependent on the parasite burden and infection time
Summary
Trichomonas vaginalis causes lesions on the cervicovaginal mucosa in women; its pathogen‐ esis 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. Gao et al Parasites & Vectors (2021) 14:603 in men, and the total estimated new cases were 156.0 million (103.4–231.2 million) worldwide in 2016 [2, 3]. This parasite causes vaginitis and cervicitis in women and asymptomatic urethritis and prostatitis in men. The role of the endoplasmic reticulum (ER) in T. vaginalis-induced apoptosis has not been elucidated
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