RESUMEN
Prostate cancer (PCa) is the second most common cancer and constitutes about 14.7% of total cancer cases. PCa is highly prevalent and more aggressive in African-American (AA) men than in European-American (EA) men. PCa tends to be highly heterogeneous, and its complex biology is not fully understood. We use metabolomics to better understand the mechanisms behind PCa progression and disparities in its clinical outcome. Adenosine deaminase (ADA) is a key enzyme in the purine metabolic pathway; it was found to be upregulated in PCa and is associated with higher-grade PCa and poor disease-free survival. The inosine-to-adenosine ratio, which is a surrogate for ADA activity was high in PCa patient urine and higher in AA PCa compared to EA PCa. To understand the significance of high ADA in PCa, we established ADA overexpression models and performed various in vitro and in vivo studies. Our studies have revealed that an acute increase in ADA expression during later stages of tumor development enhances in vivo growth in multiple pre-clinical models. Further analysis revealed that mTOR signaling activation could be associated with this tumor growth. Chronic ADA overexpression shows alterations in the cells' adhesion machinery and a decrease in cells' ability to adhere to the extracellular matrix in vitro. Losing cell-matrix interaction is critical for metastatic dissemination which suggests that ADA could potentially be involved in promoting metastasis. This is supported by the association of higher ADA expression with higher-grade tumors and poor patient survival. Overall, our findings suggest that increased ADA expression may promote PCa progression, specifically tumor growth and metastatic dissemination.
RESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
An improved understanding of the biochemical alterations that accompany tumor progression and metastasis is necessary to inform the next generation of diagnostic tools and targeted therapies. Metabolic reprogramming is known to occur during the epithelial-mesenchymal transition (EMT), a process that promotes metastasis. Here, we identify metabolic enzymes involved in extracellular matrix remodeling that are upregulated during EMT and are highly expressed in patients with aggressive mesenchymal-like breast cancer. Activation of EMT significantly increases production of hyaluronic acid, which is enabled by the reprogramming of glucose metabolism. Using genetic and pharmacological approaches, we show that depletion of the hyaluronic acid precursor UDP-glucuronic acid is sufficient to inhibit several mesenchymal-like properties including cellular invasion and colony formation in vitro, as well as tumor growth and metastasis in vivo. We found that depletion of UDP-glucuronic acid altered the expression of PPAR-gamma target genes and increased PPAR-gamma DNA-binding activity. Taken together, our findings indicate that the disruption of EMT-induced metabolic reprogramming affects hyaluronic acid production, as well as associated extracellular matrix remodeling and represents pharmacologically actionable target for the inhibition of aggressive mesenchymal-like breast cancer progression.
Asunto(s)
Neoplasias de la Mama/patología , Ácido Hialurónico/biosíntesis , Uridina Difosfato Glucosa Deshidrogenasa/metabolismo , Animales , Mama/patología , Línea Celular Tumoral , Embrión de Pollo , Membrana Corioalantoides , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Matriz Extracelular/patología , Femenino , Técnicas de Silenciamiento del Gen , Humanos , PPAR gamma/metabolismo , RNA-Seq , Análisis de Matrices Tisulares , Uridina Difosfato Glucosa Deshidrogenasa/genética , Uridina Difosfato Ácido Glucurónico/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Elimination of heavy metals from contaminated streams is of prime concern due to their ability to cause toxic chaos with the metabolism of flora and fauna alike. Use of advanced nano-engineered technologies such as the innovative combination of surface chemistry, chemical engineering fundamentals and nanotechnology opens up particularly attractive horizons towards treatment of heavy metal contaminated water resources. The obtained product of surface engineered nanoadsorbent produced has successfully proven to show rapid adsorption rate and superior sorption efficiency towards the removal of a wide range of defiant heavy metal contaminants in wastewater. The use of these materials in water treatment results in markedly improved performance features like large surface area, good volumetric potential, extra shelf-lifetime, less mechanical stress, stability under operational conditions with excellent sorption behaviour, no secondary pollution, strong chelating capabilities and they are easy to recover and reuse. This review intends to serve as a one-stop-reference by bringing together all the recent research works on nanoparticles synthesis and its advantages as adsorbents in the treatment of heavy metal polluted wastewater that have so far been undertaken, thereby providing researchers with a deep insight and bridging the gap between past, present and future of the elegant nanosorbents.
