Search Results (10)

Rosavin, a phenylpropanoid in Rhodiola rosea’s rhizome, and an adaptogen, is known for enhancing the body’s response to environmental stress. It significantly affects cellular metabolism in health and many diseases, particularly influencing bone tissue metabolism. In vitro, rosavin inhibits osteoclastogenesis, disrupts F-actin ring formation, and reduces the expression of osteoclastogenesis-related genes such as cathepsin K, calcitonin receptor (CTR), tumor necrosis factor receptor-associated factor 6 (TRAF6), tartrate-resistant acid phosphatase (TRAP), and matrix metallopeptidase 9 (MMP-9). It also impedes the nuclear factor of activated T-cell cytoplasmic 1 (NFATc1), c-Fos, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways and blocks phosphorylation processes crucial for bone resorption. Moreover, rosavin promotes osteogenesis and osteoblast differentiation and increases mouse runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) expression. In vivo studies show its effectiveness in enhancing bone mineral density (BMD) in postmenopausal osteoporosis (PMOP) mice, restraining osteoclast maturation, and increasing the active osteoblast percentage in bone tissue. It modulates mRNA expressions by increasing eukaryotic translation elongation factor 2 (EEF2) and decreasing histone deacetylase 1 (HDAC1), thereby activating osteoprotective epigenetic mechanisms, and alters many serum markers, including decreasing cross-linked C-telopeptide of type I collagen (CTX-1), tartrate-resistant acid phosphatase 5b (TRACP5b), receptor activator for nuclear factor κ B ligand (RANKL), macrophage-colony-stimulating factor (M-CSF), and TRAP, while increasing alkaline phosphatase (ALP) and OCN. Additionally, when combined with zinc and probiotics, it reduces pro-osteoporotic matrix metallopeptidase 3 (MMP-3), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α), and enhances anti-osteoporotic interleukin 10 (IL-10) and tissue inhibitor of metalloproteinase 3 (TIMP3) expressions. This paper aims to systematically review rosavin’s impact on bone tissue metabolism, exploring its potential in osteoporosis prevention and treatment, and suggesting future research directions. Full article

Age-related macular degeneration (AMD) is the leading cause of severe vision loss and blindness in elderly people worldwide. The damage to the retinal pigment epithelium (RPE) triggered by oxidative stress plays a central role in the onset and progression of AMD and results from the excessive accumulation of reactive oxygen species (ROS) produced mainly by mitochondria. Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial molecular chaperone that contributes to the maintenance of mitochondrial integrity by decreasing the production and accumulation of ROS. The present study aimed to evaluate the presence and the role of TRAP1 in the RPE. Here, we report that TRAP1 is expressed in human adult retinal pigment epithelial cells and is located mainly in the mitochondria. Exposure of RPE cells to hydrogen peroxide decreases the levels of TRAP1. Furthermore, TRAP1 silencing increases intracellular ROS production and decreases mitochondrial respiratory capacity without affecting cell proliferation. Together, these findings offer novel insights into TRAP1 functions in RPE cells, opening possibilities to develop new treatment options for AMD. Full article

Tumor necrosis factor receptor-associated protein 1 (TRAP1), also known as heat shock protein 75 (HSP75), is a member of the heat shock protein 90 (HSP90) chaperone family that resides mainly in the mitochondria. As a mitochondrial molecular chaperone, TRAP1 supports protein folding and contributes to the maintenance of mitochondrial integrity even under cellular stress. TRAP1 is a cellular regulator of mitochondrial bioenergetics, redox homeostasis, oxidative stress-induced cell death, apoptosis, and unfolded protein response (UPR) in the endoplasmic reticulum (ER). TRAP1 has attracted increasing interest as a therapeutical target, with a special focus on the design of TRAP1 specific inhibitors. Although TRAP1 was extensively studied in the oncology field, its role in central nervous system cells, under physiological and pathological conditions, remains largely unknown. In this review, we will start by summarizing the biology of TRAP1, including its structure and related pathways. Thereafter, we will continue by debating the role of TRAP1 in the maintenance of redox homeostasis and protection against oxidative stress and apoptosis. The role of TRAP1 in neurodegenerative disorders will also be discussed. Finally, we will review the potential of TRAP1 inhibitors as neuroprotective drugs. Full article

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory syndrome characterized by prolonged and recurrent episodes of fever, abdominal and/or chest pain, arthralgia, myalgia, and erythematous rash. TRAPS is associated with heterozygous variants in the TNFRSF1A gene, which encodes the TNFR1 (tumor necrosis factor receptor 1) receptor. Disease-causing variants are found exclusively in the extracellular domain of TNFR1 and affect receptor structure and binding to the TNF ligand. The precise mechanism of the disease is still unclear, but it is thought that intracellular accumulation of misfolded mutant protein leads to endoplasmic reticulum stress and enhanced inflammatory responses through constitutive activation of various immune pathways. Other possible mechanisms contributing to the disease pathogenesis include defective receptor shedding, TNF-induced cell death, production of reactive oxygen species, and autophagy impairment. Patients’ leucocytes are hyperresponsive to stimulation and produce elevated levels of proinflammatory cytokines. Systemic autoimmune (AA) amyloidosis is an important cause of morbidity and mortality in TRAPS. Over the last two decades, new therapies have changed the progression and outcome of the disease. In this review, we summarize clinical data from 209 patients with validated pathogenic variants reported in the literature and discuss TRAPS diagnosis, pathogenesis, and treatment options. Full article

Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness. Full article

Metabolic reprogramming, carried out by cancer cells to rapidly adapt to stress such as hypoxia and limited nutrient conditions, is an emerging concepts in tumor biology, and is now recognized as one of the hallmarks of cancer. In contrast with conventional views, based on the classical Warburg effect, these metabolic alterations require fully functional mitochondria and finely-tuned regulations of their activity. In turn, the reciprocal regulation of the metabolic adaptations of cancer cells and the microenvironment critically influence disease progression and response to therapy. This is also realized through the function of specific stress-adaptive proteins, which are able to relieve oxidative stress, inhibit apoptosis, and facilitate the switch between metabolic pathways. Among these, the molecular chaperone tumor necrosis factor receptor associated protein 1 (TRAP1), the most abundant heat shock protein 90 (HSP90) family member in mitochondria, is particularly relevant because of its role as an oncogene or a tumor suppressor, depending on the metabolic features of the specific tumor. This review highlights the interplay between metabolic reprogramming and cancer progression, and the role of mitochondrial activity and oxidative stress in this setting, examining the possibility of targeting pathways of energy metabolism as a therapeutic strategy to overcome drug resistance, with particular emphasis on natural compounds and inhibitors of mitochondrial HSP90s. Full article

Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a heat shock protein 90 (HSP90) molecular chaperone overexpressed in 60–70% human colorectal carcinomas (CRCs) and the co-upregulation of TRAP1 and associated 6-related proteins identifies metastatic CRCs with poor prognosis. Since the molecular mechanisms responsible for TRAP1 regulation are still unknown, the significance of TRAP1 gene copy number (CN) and the role of post-transductional protein modifications were addressed. TRAP1 gene aneuploidy accounted for 34.5% of cases in a cohort of 58 human CRCs and TRAP1 CN correlated with its mRNA and protein expression, suggesting that transcriptional mechanisms are responsible for TRAP1 upregulation. Furthermore, the analysis of the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium/The Cancer Genome Atlas (CPTAC/TCGA) CRC database showed that TRAP1 polysomy significantly correlates with lymph node involvement. However, a subgroup of tumors showed TRAP1 protein levels independent from its CN. Of note, a direct correlation was observed between TRAP1 protein levels and the expression of S-nitrosoglutathione reductase (GSNOR), a denitrosylase involved in the regulation of protein S-nitrosylation. Furthermore, CRC cell lines exposed to hypoxia or dichloroacetate treatment showed the downregulation of TRAP1 upon GSNOR silencing and this resulted in increased TRAP1 mono/polyubiquitination. These data suggest that transcriptional and post-transductional mechanisms account for TRAP1 expression in human CRCs and GSNOR protects TRAP1 from S-nitrosylation and consequent proteasome degradation mostly in conditions of stress. Full article

Cholesterol is a pivotal factor for cancer cells to entertain their relentless growth. In this case, we provide a novel strategy to inhibit tumor growth by simultaneous activation of liver-X-receptors and interference with Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1). Informed by a transcriptomic and subsequent gene set enrichment analysis, we demonstrate that inhibition of TRAP1 results in suppression of the cholesterol synthesis pathway in stem-like and established glioblastoma (GBM) cells by destabilizing the transcription factor SREBP2. Notably, TRAP1 inhibition induced cell death, which was rescued by cholesterol and mevalonate. Activation of liver X receptor (LXR) by a clinically validated LXR agonist, LXR623, along with the TRAP1 inhibitor, gamitrinib (GTPP), results in synergistic reduction of tumor growth and cell death induction in a broad range of solid tumors, which is rescued by exogenous cholesterol. The LXR agonist and TRAP1 inhibitor mediated cell death is regulated at the level of Bcl-2 family proteins with an elevation of pro-apoptotic Noxa. Silencing of Noxa and its effector BAK attenuates cell death mediated by the combination treatment of LXR agonists and TRAP1 inhibition. Combined inhibition of TRAP1 and LXR agonists elicits a synergistic activation of the integrated stress response with an increase in activating transcription factor 4 (ATF4) driven by protein kinase RNA-like endoplasmic reticulum kinase (PERK). Silencing of ATF4 attenuates the increase of Noxa by using the combination treatment. Lastly, we demonstrate in patient-derived xenografts that the combination treatment of LXR623 and gamitrinib reduces tumor growth more potent than each compound. Taken together, these results suggest that TRAP1 inhibition and simultaneous activation of LXR might be a potent novel treatment strategy for solid malignancies. Full article

Metabolic reprogramming is an important issue in tumor biology. An unexpected inter- and intra-tumor metabolic heterogeneity has been strictly correlated to tumor outcome. Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a molecular chaperone involved in the regulation of energetic metabolism in cancer cells. This protein is highly expressed in several cancers, such as glioblastoma, colon, breast, prostate and lung cancers and is often associated with drug resistance. However, TRAP1 is also downregulated in specific tumors, such as ovarian, bladder and renal cancers, where its lower expression is correlated with the worst prognoses and chemoresistance. TRAP1 is the only mitochondrial member of the Heat Shock Protein 90 (HSP90) family that directly interacts with respiratory complexes, contributing to their stability and activity but it is still unclear if such interactions lead to reduced or increased respiratory capacity. The role of TRAP1 is to enhance or suppress oxidative phosphorylation; the effects of such regulation on tumor development and progression are controversial. These observations encourage the study of the mechanisms responsible for the dualist role of TRAP1 as an oncogene or oncosuppressor in specific tumor types. In this review, TRAP1 puzzling functions were recapitulated with a special focus on the correlation between metabolic reprogramming and tumor outcome. We wanted to investigate whether metabolism-targeting drugs can efficiently interfere with tumor progression and whether they might be combined with chemotherapeutics or molecular-targeted agents to counteract drug resistance and reduce therapeutic failure. Full article

In eukaryotic cells, mitochondria are self-reproducing organelles with their own DNA and they play a central role in adenosine triphosphate (ATP) synthesis by respiration. Increasing evidence indicates that mitochondria also have critical and multiple functions in the initiation of cell differentiation, cell-type determination, cell movement, and pattern formation. This has been most strikingly realized in development of the cellular slime mold Dictyostelium. For example, the expression of the mitochondrial ribosomal protein S4 (mt-rps4) gene is required for the initial differentiation. The Dictyostelium homologue (Dd-TRAP1) of TRAP-1 (tumor necrosis receptor-associated protein 1), a mitochondrial molecular chaperone belonging to the Hsp90 family, allows the prompt transition of cells from growth to differentiation through a novel prestarvation factor (PSF-3) in growth medium. Moreover, a cell-type-specific organelle named a prespore-specific vacuole (PSV) is constructed by mitochondrial transformation with the help of the Golgi complex. Mitochondria are also closely involved in a variety of cellular activities including CN-resistant respiration and apoptosis. These mitochondrial functions are reviewed in this article, with special emphasis on the regulation of Dictyostelium development. Full article