Effects of Forkhead box O1 on lipopolysaccharide‑induced mitochondrial dysfunction in human cervical squamous carcinoma SiHa cells

Abstract Background: Human trichomoniasis is one of the most common sexually transmitted infections; however, its pathogenesis remains unclear. Here, we investigated the role of the endoplasmic reticulum (ER) in apoptosis induction by T. vaginalis in human cervical epithelial SiHa cellsMethods: We evaluated the cytotoxicity, apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), ER stress response, and Bcl-2 family protein expressions using LDH assay, immunocytochemistry, flow cytometry, JC-1 dye staining, and western blotting.Results: T. vaginalis induced LDH-dependent cytotoxicity, mitochondrial ROS production, and apoptosis in SiHa cells, parasite burden- and infection time-dependently. T. vaginalis also induced ER stress response and mitochondrial dysfunction, such as MMP depolarization and imbalance in levels of 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, ROS production, mitochondrial dysfunction, and ER stress response in a dose-dependent manner. These data suggested that SiHa cell apoptosis is affected by ROS and ER stress after T. gondii infection. In addition, T. vaginalis induced ASK1 and JNK phosphorylation in SiHa cells, however 4-PBA or SP600125 (JNK inhibitor) pretreatment significantly attenuated ASK1/JNK phosphorylation, mitochondrial dysfunction, apoptosis, and ER stress response in SiHa cells, dose-dependently.Conclusions: T. vaginalis induces mitochondrial apoptosis via ROS and parasite-mediated ER stress via the IRE1/ASK1/JNK/Mcl-1 pathways, and also induces ER stress response directly and mitochondrial ROS-dependently in human cervical epithelial SiHa cells, thus, T. vaginalis induces apoptosis via ROS and ER stress through ER-mitochondria crosstalk in human cervical epithelial cells. These results expand our understanding of the molecular mechanisms underlying the pathogenesis of human trichomoniasis.

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The vitamin D receptor (VDR) protects pancreatic beta cells against Forkhead box class O1 (FOXO1)-induced mitochondrial dysfunction and cell apoptosis

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2019.109170 ◽

2019 ◽

Vol 117 ◽

pp. 109170 ◽

Cited By ~ 5

Author(s):

Chen Chen ◽

Yuming Luo ◽

Yajuan Su ◽

Lichen Teng

Keyword(s):

Vitamin D ◽

Mitochondrial Dysfunction ◽

Beta Cells ◽

Vitamin D Receptor ◽

Cell Apoptosis ◽

Pancreatic Beta Cells ◽

Forkhead Box

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Carnosine Inhibits the Proliferation of Human Cervical Gland Carcinoma Cells Through Inhibiting Both Mitochondrial Bioenergetics and Glycolysis Pathways and Retarding Cell Cycle Progression

Integrative Cancer Therapies ◽

10.1177/1534735416684551 ◽

2016 ◽

Vol 17 (1) ◽

pp. 80-91 ◽

Cited By ~ 5

Author(s):

Yun Bao ◽

Saidan Ding ◽

Jiaoyan Cheng ◽

Yuan Liu ◽

Bingyu Wang ◽

...

Keyword(s):

Hela Cells ◽

Inhibitory Action ◽

Squamous Carcinoma ◽

Underlying Mechanism ◽

Carcinoma Cells ◽

Mitochondrial Bioenergetics ◽

Squamous Carcinoma Cells ◽

Siha Cells ◽

Cervical Gland ◽

Gland Carcinoma

Carnosine has been demonstrated to play an antitumorigenic role in certain types of cancer. However, its underlying mechanism is unclear. In this study, the roles of carnosine in cell proliferation and its underlying mechanism were investigated in the cultured human cervical gland carcinoma cells HeLa and cervical squamous carcinoma cells SiHa. The results showed that carnosine exerted a significant inhibitory effect on the proliferation of HeLa cells, whereas its inhibitory action on the proliferation of SiHa cells was much weaker. Carnosine decreased the ATP content through inhibiting both mitochondrial respiration and glycolysis pathways in cultured HeLa cells but not SiHa cells. Carnosine reduced the activities of isocitrate dehydrogenase and malate dehydrogenase in TCA (tricarboxylic acid) cycle and the activities of mitochondrial electron transport chain complex I, II, III, and IV in HeLa cells but not SiHa cells. Carnosine also decreased the mRNA and protein expression levels of ClpP, which plays a key role in maintaining the mitochondrial function in HeLa cells. In addition, carnosine induced G1 arrest by inhibiting the G1-S phase transition in both HeLa and SiHa cells. Taken together, these findings suggest that carnosine has a strong inhibitory action on the proliferation of human cervical gland carcinoma cells rather than cervical squamous carcinoma cells. Mitochondrial bioenergetics and glycolysis pathways and cell cycle may be involved in the carnosine action on the cell proliferation in cultured human cervical gland carcinoma cells HeLa.

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

Parasites & Vectors ◽

10.1186/s13071-021-05098-2 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Fei Fei Gao ◽

Juan-Hua Quan ◽

Min A. Lee ◽

Wei Ye ◽

Jae-Min Yuk ◽

...

Keyword(s):

Stress Response ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Trichomonas Vaginalis ◽

Dependent Manner ◽

Ros Production ◽

Er Stress Response ◽

Siha Cells ◽

Mitochondrial Ros ◽

Family Protein

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

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Mitochondrion-Directed Nanoparticles Loaded with a Natural Compound and a microRNA for Promoting Cancer Cell Death via the Modulation of Tumor Metabolism and Mitochondrial Dynamics

Pharmaceutics ◽

10.3390/pharmaceutics12080756 ◽

2020 ◽

Vol 12 (8) ◽

pp. 756 ◽

Cited By ~ 1

Author(s):

Yu-Li Lo ◽

Chen-Shen Wang ◽

Yen-Chun Chen ◽

Tse-Yuan Wang ◽

Yih-Hsin Chang ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Natural Compound ◽

Mitochondrial Dynamics ◽

Biological Fluid ◽

Combined Treatment ◽

Squamous Carcinoma ◽

Tumor Metabolism ◽

Apoptosis Resistance ◽

Human Tongue

Mitochondrial dysfunction may cause cancer and metabolic syndrome. Ellagic acid (abbreviated as E), a phytochemical, possesses anticancer activity. MicroRNA 125 (miR-125) may regulate metabolism. However, E has low aqueous solubility, and miR-125 is unstable in a biological fluid. Hence, this study aimed to develop nanoparticle formulations for the co-treatment of miR-125 and E. These nanoparticles were modified with one mitochondrion-directed peptide and a tumor-targeted ligand, and their modulating effects on mitochondrial dysfunction, antitumor efficacy, and safety in head and neck cancer (HNC) were evaluated. Results revealed that miR-125- and E-loaded nanoparticles effectively targeted cancer cells and intracellular mitochondria. The co-treatment significantly altered cellular bioenergetics, lipid, and glucose metabolism in human tongue squamous carcinoma SAS cells. This combination therapy also regulated protein expression associated with bioenergenesis and mitochondrial dynamics. These formulations also modulated multiple pathways of tumor metabolism, apoptosis, resistance, and metastasis in SAS cells. In vivo mouse experiments showed that the combined treatment of miR-125 and E nanoparticles exhibited significant hypoglycemic and hypolipidemic effects. The combinatorial therapy of E and miR-125 nanoparticles effectively reduced SAS tumor growth. To our best knowledge, this prospective study provided a basis for combining miRNA with a natural compound in nanoformulations to regulate mitochondrial dysfunction and energy metabolism associated with cancer.

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