June 20, 2021

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A new mechanism for ROS to regulate the occurrence of uveal melanoma

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A new mechanism for ROS to regulate the occurrence of uveal melanoma

A new mechanism for ROS to regulate the occurrence of uveal melanoma

 

Research team reveals a new mechanism for ROS to regulate the occurrence of uveal melanoma, and proposes new insights on the application of nanomaterials in tumor diagnosis. 

Recently, Professor Fan Xianqun’s team has made important progress in the development of nanometer diagnostic and therapeutic reagents for tumors.

This study found for the first time that nanomaterials can increase the level of Reactive Oxygen Species (ROS) in Uvealmelanoma (UM) cells. ROS mediated by different concentrations of nanomaterials have different effects on the malignant growth of UM cells. A certain amount of ROS can activate the mTOR signaling pathway in UM cells and enhance amino acid metabolism.

This research has very important reference value for the reasonable selection of the safe concentration of nanomaterials in tumor diagnosis and treatment applications.

The results of the study were recently officially published in the top international academic journal Advanced Science under the title “Dose Dependent Carbon Dot Induced ROS Promote Uveal Melanoma Cell Tumorigenicity via Activation of mTOR Signaling and Glutamine Metabolism”.

ROS are mainly by-products produced by cell metabolism (such as superoxide anions, H2O2, hydroxyl radicals, hydroxyl ions, etc.). When the balance between ROS and antioxidants (such as ascorbic acid, glutathione, etc.) in the cell is broken, oxidative stress will occur, which peroxidizes the biological macromolecules in the cell, thereby damaging the cell. Due to the strong metabolism of tumor cells, ROS is significantly increased in many types of tumors. For this reason, a large number of studies have used nanomaterials to control the excessive ROS produced in tumor cells to kill tumors. However, ROS can also play an important role as an induction or signaling molecule in tumor formation, malignant transformation, and chemotherapy resistance. Whether the ROS induced by nanomaterials will have an unknown effect on the occurrence and development of tumors, this key question plays an important role in the diagnosis and treatment of tumors with nanomaterials, so it is urgent to be clarified.

UM is the most common intraocular malignant tumor in adults. It is highly malignant, easy to metastasize, and has a poor prognosis. It seriously threatens the patient’s vision and life safety. Uveal melanoma originates from melanocytes in the choroid, ciliary body, or iris. Due to UV exposure and the production of melanin, melanocytes are more susceptible to the regulation of ROS and increase the risk of melanoma than other normal cells. If nanomaterial-mediated ROS technology is used for early detection or co-treatment of UM, there is a risk of enhancing tumor occurrence and development. Therefore, the team used different concentrations of carbon dot nanomaterials to induce UM cells to produce different levels of ROS, and comprehensively analyzed whether it can play a role as a signal molecule and have different effects on the occurrence and development of tumor cells, and explained this based on the perspective of tumor metabolism. The mechanism behind a phenomenon.

The research team first combined ROS fluorescence display technology and intracellular redox state detection technology to analyze the intracellular ROS levels, antioxidant capacity and cell phenotype changes of UM cells after short-term stimulation of carbon dots (C-dots), and the results showed that different concentrations The antioxidant capacity of UM cells treated with C-dots is different. A low dose (25-100 μg/mL) of C-dots can increase the level of ROS in UM cells, and at the same time, the antioxidant capacity of cells is enhanced, and the redox level is rebalanced.

The proliferation, migration, invasion, and tumor formation ability of UM cells in vitro is enhanced. After adding antioxidant NAC or Toc to eliminate the influence of ROS, the promotion effect of C-dots disappears, while the high dose (200 μg/mL) C-dots produces ROS breaks the redox balance of cells and peroxidizes biological macromolecules, leading to apoptosis of UM cells. This result has been verified in both the zebrafish xenograft tumor model and the intraocular tumor-bearing mouse model in situ.

In order to explore the mechanism behind this phenomenon, the research team applied non-targeted metabolomics technology (LC-MS) combined with glutamine metabolism-related gene mRNA expression profiles and found that ROS induced by C-dots activates the Akt/mTOR pathway and promotes gluten metabolism. Aminoamide metabolism accelerates the hydrolysis of glutamine into glutamic acid, provides raw materials for the synthesis of glutathione, and regulates the redox balance of cells.

At the same time, glutamic acid can further generate α-ketoglutarate through the action of transaminase, which enters the tricarboxylic acid cycle to generate more ATP, thereby promoting the growth of tumor cells.

 

(source:internet, reference only)


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