Biology subjects

Skvortsova, I.-I.

Publications and source records attributed to Skvortsova, I.-I..

3 recordsLinked to original sources

bioRxiv2025

Glutamine transporters regulate prostate cancer radiosensitivity through NUPR1-mediated stress response

BackgroundMetabolic and stress response adaptations in prostate cancer (PCa) mediate tumor resistance to radiation therapy (RT). Our study investigated the roles of glutamine (Gln) transporters SLC1A5, SLC7A5, and SLC38A1 in regulating NUPR1-mediated stress response, PCa cell survival, metabolic reprogramming, and response to RT. MethodsThe radiosensitizing potential of GLS inhibition with CB-839 was analyzed in prostate cancer xenograft models. The level of gene expression was analyzed by RNA sequencing and RT-qPCR in the established cell lines or patient-derived tumor and adjacent non-cancerous tissues. Phosphoproteomic analysis was employed to identify the underlying signaling pathways. The publicly available PCa patient genesets, and a geneset for the patients treated with RT were analyzed by SUMO software. The key parameters of mitochondrial functions were measured by Seahorse analysis. Analysis of the general oxidative stress level and mitochondrial superoxide detection were conducted using flow cytometry. {gamma}H2A.X foci analysis was used to assess the DNA double strand break. Relative cell sensitivity to RT was evaluated by radiobiological clonogenic assays. Aldefluor assay and sphere-forming analysis were used to determine cancer stem cell (CSC) phenotype. ResultsDepletion of these transporters led to reduced cell viability, altered ROS levels, and enhanced radiosensitivity in PCa cell lines. Functional assays revealed that targeting these transporters decreases CSC properties, impairs cell cycle progression, and deregulates mitochondrial energy metabolism. Our findings indicate that the Gln transporters mediate the adaptation of tumor cells to nutrient stress, while NUPR1 promotes cellular survival under metabolic and genotoxic stress. Targeting SLC1A5, SLC7A5, SLC38A1, and NUPR1 radiosensitizes PCa by disrupting metabolic adaptations and stress responses. Besides, CB-839, a glutaminase (GLS) inhibitor, combined with RT, demonstrated a synergistic effect with radiotherapy in vivo, significantly delaying tumor growth. We found that GLS gene expression levels are significantly associated with clinical outcomes in PCa patients treated with RT. ConclusionsOur work underscores the role of Gln transporters and the NUPR1-mediated stress response induced by Gln deficiency in PCa cell survival, stemness, mitochondrial functions and radioresistance. Our findings provide a potential therapeutic in vivo strategy to enhance the efficacy of RT and improve treatment outcomes for PCa patients.

cancer biology↗

bioRxiv2021

GLS-driven glutamine catabolism contributes to prostate cancer radiosensitivity by regulating the redox state, stemness and ATG5-mediated autophagy

Radiotherapy is one of the curative treatment options for localized prostate cancer (PCa). The curative potential of radiotherapy is mediated by irradiation-induced oxidative stress and DNA damage in tumor cells. However, PCa radiocurability can be impeded by tumor resistance mechanisms and normal tissue toxicity. Metabolic reprogramming is one of the major hallmarks of tumor progression and therapy resistance. Here, we found that radioresistant PCa cells and prostate cancer stem cells (CSCs) have a high glutamine demand. Glutaminase (GLS)-driven catabolism of glutamine serves not only for energy production but also for the maintenance of the redox state. Consequently, glutamine depletion or inhibition of critical regulators of glutamine utilization, such as glutaminase (GLS) and the transcription factor MYC results in PCa radiosensitization. On the contrary, we found that a combination of glutamine metabolism inhibitors with irradiation does not cause toxic effects on nonmalignant prostate cells. Glutamine catabolism contributes to the maintenance of CSCs through regulation of the alpha-ketoglutarate (-KG)-dependent chromatin-modifying dioxygenase. The lack of glutamine results in the inhibition of CSCs with a high aldehyde dehydrogenase (ALDH) activity, decreases the frequency of the CSC populations in vivo and reduces tumor formation in xenograft mouse models. Moreover, this study shows that activation of the ATG5-mediated autophagy in response to a lack of glutamine is a tumor survival strategy to withstand radiation-mediated cell damage. In combination with autophagy inhibition, the blockade of glutamine metabolism might be a promising strategy for PCa radiosensitization. High blood levels of glutamine in PCa patients significantly correlate with a shorter prostate-specific antigen (PSA) doubling time. Furthermore, high expression of critical regulators of glutamine metabolism, GLS1 and MYC, is significantly associated with a decreased progression-free survival in PCa patients treated with radiotherapy. Our findings demonstrate that GLS-driven glutaminolysis is a prognostic biomarker and therapeutic target for PCa radiosensitization.

cancer biology↗

bioRxiv2020

ETV7 regulates breast cancer stem-like cell plasticity by repressing IFN-response genes

Cancer stem cells (CSCs) represent a population of cells within the tumor able to drive tumorigenesis and known to be highly resistant to conventional chemotherapy and radiotherapy. In this work, we show a new role for ETV7, a transcriptional repressor member of the ETS family, in promoting breast cancer stem-like cells plasticity and resistance to chemo- and radiotherapy in breast cancer (BC) cells. We observed that MCF7 and T47D BC-derived cells stably over-expressing ETV7 showed reduced sensitivity to the chemotherapeutic drug 5-Flouororuacil and to radiotherapy, accompanied by an adaptive proliferative behavior observed in different culture conditions. We further noticed that alteration of ETV7 expression could significantly affect the population of breast CSCs, measured by CD44+/CD24low cell population and mammosphere formation efficiency. By transcriptome profiling, we identified a signature of Interferon-responsive genes significantly repressed in cells over-expressing ETV7, which could be responsible for the increase in the breast CSCs population, as this could be partially reverted by the treatment with IFN-{beta}. Lastly, we show that the expression of the IFN-responsive genes repressed by ETV7 could have prognostic value in breast cancer, as low expression of these genes was associated with a worse prognosis. Therefore, we propose a novel role for ETV7 in breast cancer stem cells plasticity and associated resistance to conventional chemotherapy and radiotherapy, which involves the repression of a group of IFN-responsive genes, potentially reversible upon IFN-{beta} treatment. We, therefore, suggest that an in-depth investigation of this mechanism could lead to novel breast CSCs targeted therapies and to the improvement of combinatorial regimens, possibly involving the therapeutic use of IFN-{beta}, with the aim of avoiding resistance development and relapse in breast cancer.

cancer biology↗