ABSTRACT
BACKGROUND: Chronic ER stress and dysfunction is a hallmark of obesity and a critical contributor to metaflammation, abnormal hormone action and altered substrate metabolism in metabolic tissues, such as liver and adipocytes. Lack of STAMP2 in lean mice induces inflammation and insulin resistance on a regular diet, and it is dysregulated in the adipose tissue of obese mice and humans. We hypothesized that the regulation of STAMP2 is disrupted by ER stress. METHODS: 3T3-L1 and MEF adipocytes were treated with ER stress inducers thapsigargin and tunicamycin, and inflammation inducer TNFα. The treatments effect on STAMP2 expression and enzymatic function was assessed. In addition, 3T3-L1 adipocytes and HEK cells were utilized for Stamp2 promoter activity investigation performed with luciferase and ChIP assays. RESULTS: ER stress significantly reduced both STAMP2 mRNA and protein expression in cultured adipocytes whereas TNFα had the opposite effect. Concomitant with loss of STAMP2 expression during ER stress, intracellular localization of STAMP2 was altered and total iron reductase activity was reduced. Stamp2 promoter analysis by reporter assays and chromatin immunoprecipitation, showed that induction of ER stress disrupts C/EBPα-mediated STAMP2 expression. CONCLUSION: These data suggest a clear link between ER stress and quantitative and functional STAMP2-deficiency.
Subject(s)
Adipocytes/metabolism , Endoplasmic Reticulum Stress , Inflammation/metabolism , Membrane Proteins/metabolism , Adipocytes/pathology , Animals , Cells, Cultured , Endoplasmic Reticulum Stress/drug effects , Inflammation/chemically induced , Membrane Proteins/analysis , Membrane Proteins/deficiency , Mice , RNA, Messenger/analysis , Thapsigargin/pharmacology , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
Six Transmembrane Protein of Prostate 2 (STAMP2) has been implicated in both prostate cancer (PCa) and metabolic disease. STAMP2 has unique anti-inflammatory and pro-metabolic properties in mouse adipose tissue, but there is limited information on its role in human metabolic tissues. Using human adipose-derived stem cells (ASCs), we report that STAMP2 expression is dramatically upregulated during adipogenesis. shRNA-mediated STAMP2 knockdown in ASCs significantly suppresses adipogenesis and interferes with optimal expression of adipogenic genes and adipocyte metabolic function. Furthermore, ASC-derived adipocyte-mediated stimulation of prostate tumor growth in nude mice is significantly reduced upon STAMP2 knockdown in ASC adipocytes. These results suggest that STAMP2 is crucial for normal ASC conversion into adipocytes and their metabolic function, as well as their ability to facilitate PCa growth in vivo.
ABSTRACT
Increased metabolic activity is a hallmark of proliferating cancer cells. One common deregulated metabolic pathway in prostate cancer is de novo lipogenesis which is highly increased in prostate cancer and is linked to poor prognosis and metastasis. Male sex hormones play an essential role in prostate cancer growth and have been shown to increase the expression and activity of several lipogenic factors, such as fatty acid synthase (FASN) and sterol regulatory element-binding proteins (SREBPs), leading to accumulation of neutral lipids in prostate cancer cells. These factors are being evaluated as potential prognostic markers and therapeutic targets in prostate cancer. Here we describe methods to directly detect and quantify accumulation of neutral lipids and assess concomitant changes in lipogenic gene expression in LNCaP prostate cancer cells.
Subject(s)
Androgens/metabolism , Lipid Metabolism/drug effects , Prostatic Neoplasms/metabolism , Androgens/pharmacology , Biological Assay , Cell Culture Techniques , Cell Line, Tumor/drug effects , Humans , Male , Microscopy, Fluorescence , Prostatic Neoplasms/pathology , Reverse Transcriptase Polymerase Chain Reaction , Tissue FixationABSTRACT
Prostate cancer is the most diagnosed noncutaneous cancer among men in Western developed countries. Nutrition and environmental factors play a major role in the onset of the disease, but the molecular details for the contribution of each factor is elusive. In an effort to better understand the basic biology of prostate cancer, we identified a new protein family that is named the 6 trans-membrane protein of prostate (STAMP) that appear to have important functions in prostate cancer. At least one member of the STAMP family is also implicated in metabolic homeostasis and nutrition response. Here, we review the current biology of the STAMP proteins and how they may be implicated in disease states including cancer and metabolic syndrome.
Subject(s)
Membrane Proteins/physiology , Neoplasm Proteins/physiology , Oxidoreductases/physiology , Prostatic Neoplasms/etiology , Animals , Antigens, Neoplasm/genetics , Antigens, Neoplasm/physiology , Humans , Male , Membrane Proteins/genetics , Mice , Neoplasm Proteins/genetics , Nutritional Physiological Phenomena , Oxidoreductases/geneticsABSTRACT
Metabolic and inflammatory pathways crosstalk at many levels, and, while required for homeostasis, interaction between these pathways can also lead to metabolic dysregulation under conditions of chronic stress. Thus, we hypothesized that mechanisms might exist to prevent overt inflammatory responses during physiological fluctuations in nutrients or under nutrient-rich conditions, and we identified the six-transmembrane protein STAMP2 as a critical modulator of this integrated response system of inflammation and metabolism in adipocytes. Lack of STAMP2 in adipocytes results in aberrant inflammatory responses to both nutrients and acute inflammatory stimuli. Similarly, in whole animals, visceral adipose tissue of STAMP2(-/-) mice exhibits overt inflammation, and these mice develop spontaneous metabolic disease on a regular diet, manifesting insulin resistance, glucose intolerance, mild hyperglycemia, dyslipidemia, and fatty liver disease. We conclude that STAMP2 participates in integrating inflammatory and metabolic responses and thus plays a key role in systemic metabolic homeostasis.
