ABSTRACT
Glioblastoma (GBM) is a highly aggressive and deadly brain cancer. Temozolomide (TMZ) is the standard chemotherapeutic agent for GBM, but the majority of patients experience recurrence and invasion of tumor cells. We investigated whether TMZ treatment of GBM cells regulates matrix metalloproteinases (MMPs), which have the main function to promote tumor cell invasion. TMZ effectively killed GL261, U343, and U87MG cells at a concentration of 500 µM, and surviving cells upregulated MMP9 expression and its activity but not those of MMP2. TMZ also elevated levels of MMP9 mRNA and MMP9 promoter activity. Subcutaneous graft tumors survived from TMZ treatment also exhibited increased expression of MMP9 and enhanced gelatinolytic activity. TMZ-mediated MMP9 upregulation was specifically mediated through the phosphorylation of p38 and JNK. This then stimulates AP-1 activity through the upregulation of c-Fos and c-Jun. Inhibition of the p38, JNK, or both pathways counteracted the TMZ-induced upregulation of MMP9 and AP-1. This study proposes a potential adverse effect of TMZ treatment for GBM: upregulation of MMP9 expression potentially associated with increased invasion and poor prognosis. This study also provides valuable insights into the molecular mechanisms by which TMZ treatment leads to increased MMP9 expression in GBM cells.
Subject(s)
Gene Expression Regulation, Neoplastic , Glioblastoma , Matrix Metalloproteinase 9 , Temozolomide , p38 Mitogen-Activated Protein Kinases , Temozolomide/pharmacology , Glioblastoma/drug therapy , Glioblastoma/metabolism , Glioblastoma/genetics , Glioblastoma/pathology , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase 9/genetics , Humans , p38 Mitogen-Activated Protein Kinases/metabolism , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , MAP Kinase Signaling System/drug effects , Antineoplastic Agents, Alkylating/pharmacology , Animals , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Transcription Factor AP-1/metabolism , Up-Regulation/drug effects , MiceABSTRACT
Hepatic steatosis and subsequent fatty liver disease are developed in response to alcohol consumption. Reactive oxygen species (ROS) are thought to play an important role in the alcoholic fatty liver disease (AFLD). However, the molecular targets of ROS and the underlying cellular mechanisms are unknown. Here, we investigate roles of peroxiredoxin III and redox regulation of phosphatase and tension homolog deleted on chromosome 10 (PTEN) in the alcoholic fatty liver. Alcohol-induced mitochondrial oxidative stress was found to contribute to reversible oxidation of PTEN, which results in Akt and MAPK hyperactivation with elevated levels of the lipogenesis regulators SREBP1c and PPARγ. Moreover, mitochondrial peroxiredoxin III was found to have antagonistic effects on lipogenesis via the redox regulation of PTEN by removing ROS, upon alcohol exposure. This study demonstrated that redox regulation of PTEN and peroxiredoxin III play crucial roles in the development of AFLD.
Subject(s)
Fatty Liver, Alcoholic , Fatty Liver, Alcoholic/genetics , Fatty Liver, Alcoholic/metabolism , Humans , Lipogenesis , Liver/metabolism , Oxidation-Reduction , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Peroxiredoxin III/metabolismABSTRACT
BACKGROUND: Existing evidence suggests that the cardiovascular morbidities are increasing among pre-hypertensive individuals compared to normal. The aim of this study was to evaluate the prevalence of prehypertension, hypertension and to identify psychosocial risk factors for prehypertension among university students in Association of South East Asian Nation (ASEAN) countries. METHODS: Based on a cross-sectional survey, the total sample included 4649 undergraduate university students (females = 65.3%; mean age 20.5, SD = 2.9, age range of 18-30 years) from 7 ASEAN countries (Indonesia, Laos, Malaysia, Myanmar, Philippines, Thailand and Vietnam). Blood pressure, anthropometric, health behaviour and psychosocial variables were measured. RESULTS: Overall, 19.0% of the undergraduate university students across ASEAN countries had prehypertension, 6.7% hypertension and 74.2% were normotensives. There was country variation in prehypertension prevalence, ranging from 11.3% in Indonesia and 11.5% in Malaysia to above 18% in Laos, Myanmar and Thailand. In multivariate analysis, sociodemographic variables (male gender, living in an upper middle income country, and living on campus or off campus on their own), nutrition and weight variables (not being underweight and obese, having once or more times soft drinks in a day and never or rarely having chocolate or candy), heavy drinking and having depressive symptoms were associated with prehypertension. CONCLUSION: The study found a high prevalence of prehypertension in ASEAN university students. Several psychosocial risk factors including male gender, obesity, soft drinks consumption, heavy drinking and depression symptoms have been identified which can help in intervention programmes.
