ABSTRACT
SELENOF is a member of the class of selenoproteins in which the amino acid selenocysteine is co-translationally inserted into the elongating peptide in response to an in-frame UGA codon located in the 3'-untranslated (3'-UTR) region of the SELENOF mRNA. Polymorphisms in the 3'-UTR are associated with an increased risk of dying from prostate cancer and these variations are functional and 10 times more frequent in the genomes of African American men. SELENOF is dramatically reduced in prostate cancer compared to benign adjacent regions. Using a prostate cancer tissue microarray, it was previously established that the reduction of SELENOF in the cancers from African American men was significantly greater than in cancers from Caucasian men. When SELENOF levels in human prostate immortalized epithelial cells were reduced with an shRNA construct, those cells acquired the ability to grow in soft agar, increased the ability to migrate in a scratch assay and acquired features of energy metabolism associated with prostate cancer. These results support a role of SELENOF loss in prostate cancer progression and further indicate that SELENOF loss and genotype may contribute to the disparity in prostate cancer mortality experienced by African American men.
Subject(s)
Cell Transformation, Neoplastic/genetics , Epithelial Cells/pathology , Prostate/pathology , Selenoproteins/genetics , Adult , Aged , Case-Control Studies , Cell Line, Transformed , Cells, Cultured , Epithelial Cells/metabolism , Genotype , Humans , Male , Middle Aged , Phenotype , Prostate/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathologyABSTRACT
OBJECTIVE: The broad goal of the research described in this study was to investigate the contributions of selenium-binding protein 1 (SBP1) loss in prostate cancer development and outcome. METHODS: SBP1 levels were altered in prostate cancer cell lines and the consequences on oxygen consumption, expression of proteins associated with energy metabolism, and cellular transformation and migration were investigated. The effects of exposing cells to the SBP1 reaction products, H2 O2 and H2 S were also assessed. In silico analyses identified potential HNF4α binding sites within the SBP1 promoter region and this was investigated using an inhibitor specific for that transcription factor. RESULTS: Using in silico analyses, it was determined that the promoter region of SBP1 contains putative binding sites for the HNF4α transcription factor. The potential for HNF4α to regulate SBP1 expression was supported by data indicating that HNF4α inhibition resulted in a dose-response increase in the levels of SBP1 messenger RNA and protein, identifying HNF4α as a novel negative regulator of SBP1 expression in prostate cancer cells. The consequences of altering the levels of SBP1 were investigated by ectopically expressing SBP1 in PC-3 prostate cancer cells, where SBP1 expression attenuated anchorage-independent cellular growth and migration in culture, both properties associated with transformation. SBP1 overexpression reduced oxygen consumption in these cells and increased the activation of AMP-activated protein kinase (AMPK), a major regulator of energy homeostasis. In addition, the reaction products of SBP1, H2 O2 , and H2 S also activated AMPK. CONCLUSIONS: Based on the obtained data, it is hypothesized that SBP1 negatively regulates oxidative phosphorylation (OXPHOS) in the healthy prostate cells by the production of H2 O2 and H2 S and consequential activation of AMPK. The reduction of SBP1 levels in prostate cancer can occur due to increased binding of HNF4α, acting as a transcriptional inhibitor to the SBP1 promoter. Consequently, there is a reduction in H2 O2 and H2 S-mediated signaling, inhibition of AMPK, and stimulation of OXPHOS and building blocks of biomolecules needed for tumor growth and progression. Other effects of SBP1 loss in tumor cells remain to be discovered.
Subject(s)
Prostatic Neoplasms/metabolism , Selenium-Binding Proteins/metabolism , AMP-Activated Protein Kinase Kinases , Cell Line, Tumor , Cell Transformation, Viral , DNA Methylation , Disease Progression , Energy Metabolism , Gene Expression Regulation, Neoplastic , Glucose/metabolism , Hepatocyte Nuclear Factor 4/genetics , Hepatocyte Nuclear Factor 4/metabolism , Humans , Hydrogen Peroxide/metabolism , Hydrogen Sulfide/metabolism , Male , Oxidative Phosphorylation , Oxygen Consumption , PC-3 Cells , Promoter Regions, Genetic , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Protein Kinases/metabolism , Selenium-Binding Proteins/deficiency , Selenium-Binding Proteins/genetics , Subcellular Fractions/metabolismABSTRACT
Selenium-binding protein 1 (SBP1) is a highly conserved protein that covalently binds selenium. SBP1 may play important roles in several fundamental physiological functions, including protein degradation, intra-Golgi transport, cell differentiation, cellular motility, redox modulation, and the metabolism of sulfur-containing molecules. SBP1 expression is often reduced in many cancer types compared to the corresponding normal tissues and low levels of SBP1 are frequently associated with poor clinical outcome. In this review, the transcriptional regulation of SBP1, the different physiological roles reported for SBP1, as well as the implications of SBP1 function in cancer and other diseases are presented.
Subject(s)
Disease , Health , Selenium-Binding Proteins/metabolism , Carcinogenesis/metabolism , Carcinogenesis/pathology , Humans , Selenium/metabolism , Selenium-Binding Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
Triple-negative breast cancer (TNBC) is a highly metastatic subtype of breast cancer that has limited therapeutic options. Thus, developing novel treatments for metastatic TNBC is an urgent need. Here, we show that nanoparticle-mediated delivery of transforming growth factor-ß1-activated kinase-1 (TAK1) inhibitor 5Z-7-Oxozeaenol can inhibit TNBC lung metastasis in most animals tested. P38 is a central signal downstream of TAK1 in TNBC cells in TAK1-mediated response to multiple cytokines. Following co-culturing with macrophages or fibroblasts, TNBC cells express interleukin-1 (IL1) or tumor necrosis factor-α (TNFα), respectively. Compared to TAK1 inhibition, suppressing IL1 signaling with recombinant IL1 receptor antagonist (IL1RA) is less efficient in reducing lung metastasis, possibly due to the additional TAK1 signals coming from distinct stromal cells. Together, these observations suggest that TAK1 may play a central role in promoting TNBC cell adaptation to the lung microenvironment by facilitating positive feedback signaling mediated by P38. Approaches targeting the key TAK1-P38 signal could offer a novel means for suppressing TNBC lung metastasis.
Subject(s)
Lactones/administration & dosage , Lung Neoplasms/secondary , MAP Kinase Kinase Kinases/metabolism , Resorcinols/administration & dosage , Triple Negative Breast Neoplasms/metabolism , Tumor Microenvironment , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Cell Line, Tumor , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Female , Humans , Interleukin-1/genetics , Interleukin-1/metabolism , Lactones/chemistry , Lung Neoplasms/metabolism , Lung Neoplasms/prevention & control , MAP Kinase Kinase Kinases/antagonists & inhibitors , MAP Kinase Kinase Kinases/genetics , Mice, Inbred BALB C , Neoplasm Metastasis , Resorcinols/chemistry , Signal Transduction/drug effects , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/physiopathology , Tumor Microenvironment/drug effects , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Currently the clinical management of breast cancer relies on relatively few prognostic/predictive clinical markers (estrogen receptor, progesterone receptor, HER2), based on primary tumor biology. Circulating biomarkers, such as circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) may enhance our treatment options by focusing on the very cells that are the direct precursors of distant metastatic disease, and probably inherently different than the primary tumor's biology. To shift the current clinical paradigm, assessing tumor biology in real time by molecularly profiling CTCs or ctDNA may serve to discover therapeutic targets, detect minimal residual disease and predict response to treatment. This review serves to elucidate the detection, characterization, and clinical application of CTCs and ctDNA with the goal of precision treatment of breast cancer.
