ABSTRACT
The primary liver cancer (PLC) is one of the leading causes of cancer-related death worldwide. The predominant form of PLC is hepatocellular carcinoma (HCC), which accounts for about 85% of all PLC. Artemisinin (ART) was clinically used as anti-malarial agents. Recently, it was demonstrated to inhibit cell growth and migration in multiple cancer types. However, the molecular mechanism underlying these anti-cancer activity remains largely unknown. Herein, it is discovered that ART dramatically suppresses HCC cell growth in vitro through arresting cell cycle progression, and represses cell migration and invasion via regulating N-cadherin-Snail-E-cadherin axis. In addition, the disruption of cellular bioenergetics contributed to ART-caused cell growth, migration and invasion inhibition. Moreover, ART (100 mg/kg, intraperitoneally) substantially inhibits HCC xenograft growth in vivo. Importantly, Hippo-YAP signal transduction is remarkably inactivated in HCC cells upon ART administration. Collectively, these data reveal a novel mechanism of ART in regulating HCC cell growth, migration, and invasion, which indicates that ART could be considered as a potential drug for the treatment of HCC.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Antineoplastic Agents, Phytogenic/pharmacology , Artemisinins/pharmacology , Cell Movement/drug effects , Cell Proliferation/drug effects , Protein Serine-Threonine Kinases/metabolism , Transcription Factors/metabolism , Animals , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Hippo Signaling Pathway , Humans , Liver Neoplasms/pathology , Male , Mice, Nude , Neoplasm Invasiveness , Signal Transduction , Xenograft Model Antitumor Assays , YAP-Signaling ProteinsABSTRACT
The aim of the present study was to explore the effects of oxidative stress induced by CoCl2 and H2O2 on the regulation of bioenergetics of esophageal squamous cell carcinoma (ESCC) cell line TE-1 and analyze its underlying mechanism. Western blot results showed that CoCl2 and H2O2 treatment of TE-1 cells led to significant reduction in mitochondrial respiratory chain complex subunits expression and increasing intracellular reactive oxygen species (ROS) production. We further found that TE-1 cells treated with CoCl2, a hypoxia-mimicking reagent, dramatically reduced the oxygen consumption rate (OCR) and increased the extracellular acidification rate (ECAR). However, H2O2 treatment decreased both the mitochondrial respiration and aerobic glycolysis significantly. Moreover, we found that H2O2 induces apoptosis in TE-1 cells through the activation of PARP, Caspase 3, and Caspase 9. Therefore, our findings indicate that CoCl2 and H2O2 could cause mitochondrial dysfunction by up-regulation of ROS and regulating the cellular bioenergy metabolism, thus affecting the survival of tumor cells.
Subject(s)
Carcinoma, Squamous Cell/pathology , Energy Metabolism/physiology , Esophageal Neoplasms/pathology , Oxidative Stress/physiology , Apoptosis/physiology , Carcinoma, Squamous Cell/metabolism , Caspase 3/metabolism , Caspase 9/metabolism , Cell Line, Tumor , Cell Survival/physiology , Esophageal Neoplasms/metabolism , Esophageal Squamous Cell Carcinoma , Humans , Mitochondria/pathology , Oxygen Consumption/physiology , Reactive Oxygen Species/metabolismABSTRACT
Mitochondrial transcription factor A (TFAM) is essential for the replication, transcription and maintenance of mitochondrial DNA (mtDNA). The role of TFAM in non-small cell lung cancer (NSCLC) remains largely unknown. Herein, we report that downregulation of TFAM in NSCLC cells resulted in cell cycle arrest at G1 phase and significantly blocked NSCLC cell growth and migration through the activation of reactive oxygen species (ROS)-induced c-Jun amino-terminal kinase(JNK)/p38 MAPK signaling and decreased cellular bioenergetics. We further found that TFAM downregulation in NSCLC cells led to increased apoptotic cell death and enhanced the sensitivity of NSCLC cells to cisplatin. Tissue microarray (TMA) data showed that elevated expression of TFAM was related to the histological grade and TNM stage of NSCLC patients. We also demonstrated that TFAM is an independent prognostic factor for overall survival of NSCLC patients. Taken together, our findings suggest that TFAM could serve as a potential diagnostic biomarker and molecular target for the treatment of NSCLC, as well as for prediction of the effectiveness of chemotherapy.
Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , DNA-Binding Proteins/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Lung Neoplasms/metabolism , MAP Kinase Signaling System , Mitochondrial Proteins/metabolism , Reactive Oxygen Species/metabolism , Transcription Factors/metabolism , Animals , Carcinogenesis , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , DNA-Binding Proteins/genetics , Down-Regulation , Female , HEK293 Cells , Heterografts , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Mice , Mice, Nude , Middle Aged , Mitochondrial Proteins/genetics , Signal Transduction , Transcription Factors/genetics , Transfection , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
ATP-dependent Lon protease within mitochondrial matrix contributes to the degradation of abnormal proteins. The oxidative or hypoxic stress which represents the stress phenotype of cancer leads to up-regulation of Lon. However, the role of Lon in bladder cancer remains undefined. Here, we found that Lon expression in bladder cancer tissues was significantly higher than those in noncancerous tissues; down-regulation of Lon in bladder cancer cells significantly blocked cancer cell proliferation via suppression c-Jun N-terminal kinase (JNK) phosphorylation due to decreased reactive oxygen species (ROS) production and enhanced the sensitivity of bladder cancer cells to chemotherapeutic agents by promoting apoptosis. We further found that Lon down-regulation in bladder cancer cells decreased cellular bioenergetics as determined by measuring aerobic respiration and glycolysis using extracellular flux analyzer. The tissue microarray (TMA) results showed that high expression of Lon was related to the T and TNM stage, as well as histological grade of bladder cancer patients. We also demonstrated that Lon was an independent prognostic factor for overall survival of bladder cancer. Taken together, our data suggest that Lon could serve as a potential diagnostic biomarker and therapeutic target for treatment of bladder cancer, as well as for prediction of the effectiveness of chemotherapy.