Biology subjects

Vichova, R.

Publications and source records attributed to Vichova, R..

3 recordsLinked to original sources

bioRxiv2026

10-Nitro-oleic acid improves survival following gamma irradiation and modulates hematopoietic and intestinal responses

Acute radiation syndrome remains a major consequence of high-dose ionizing radiation exposure, and effective pharmacological countermeasures are limited. Nitro-fatty acids possess anti-inflammatory and cytoprotective properties, suggesting potential effectiveness in radiation injury. Here, we investigated the radioprotective effects of 10-nitro-oleic acid (10-NO2OA) in mouse models of total body irradiation (TBI). C57BL/6 mice were exposed to either sublethal (4 Gy) or LD50-level (7.5 Gy) gamma irradiation and treated with 10-NO2OA according to pre-irradiation, post-irradiation, or combined treatment regimens. Survival, hematological responses, bone marrow cells (BMCs)/colony-forming units (CFU), plasma granulocyte colony-stimulating factor (G-CSF), NRF2-responsive signaling, and intestinal responses were evaluated. Administration of 10-NO2OA before and after irradiation significantly improved 30-day survival following 7.5 Gy TBI (57% vs. 20% in vehicle-treated controls). In contrast, post-irradiation treatment alone was ineffective, whereas pre-irradiation treatment alone produced a non-significant trend toward improved survival. The protective effect was absent in BALB/c mice, indicating strain dependence. Although 10-NO2OA did not prevent long-term radiation-induced cytopenia, it increased neutrophil and platelet counts, elevated plasma G-CSF levels shortly after irradiation, and transiently enhanced BMC counts. In irradiated BMCs, 10-NO2OA activated NRF2-responsive gene expression in vitro and in vivo. Exploratory intestinal analyses revealed improved macroscopic appearance and partial restoration of irradiation-suppressed cytokine and growth factor production. In conclusion, 10-NO2OA improves survival following LD50-level gamma irradiation and is associated with modulation of hematopoietic, cytoprotective, and intestinal responses. These findings identify 10-NO2OA as a promising candidate radioprotective agent and support a multifactorial mechanism of action.

pharmacology and toxicology↗

bioRxiv2025

Translational control of AMPK activity in melanoma

The eIF4F translation initiation complex controls ERK MAPK signaling in malignant melanomas with BRAF and NRAS mutations. It also contributes to the development of melanoma resistance to therapies targeting BRAF and MEK kinases. Here, we uncovered a critical role for eIF4F in regulating the main cellular metabolic sensor, AMP-activated protein kinase (AMPK). In melanoma cells with the most common BRAF V600E mutation, ERK and AMPK pathway activities were reported as mutually exclusive. This is because BRAF-driven ERK activity negatively impacts LKB1-mediated canonical AMPK activation. However, we observed that eIF4F inhibition can stimulate AMPK activity in melanoma cells, both in vitro and in vivo, despite concomitant ERK hyperactivation. Notably, the protein levels of LKB1 and its co-factor MO25 were sensitive to eIF4F inhibition, indicating a non-canonical LKB1-independent mechanism of AMPK activation. In a proteomic screen, we aimed to identify eIF4F roles in melanoma cell physiology beyond the MAPK pathway. We found that the eIF4F function is essential for maintaining cellular levels of key cell cycle and metabolic regulators, including CDK1, CDK2, TYMS, and UHRF1. Importantly, we also identified the protein phosphatase PP2A as a new eIF4F target. Our subsequent analyses showed that inhibition or siRNA-mediated knockdown of PP2A increases AMPK activity in melanoma cells, independent of LKB1. This data shows that PP2A plays a significant role in regulating AMPK activity in melanoma. Thus, eIF4F inhibition not only impairs canonical AMPK activators but also downregulates PP2A, which negatively regulates AMPK dynamics. Collectively, our data highlight a dual role of eIF4F in the control of AMPK in BRAF-mutant melanoma cells. It maintains the canonical AMPK signaling pathway while simultaneously limiting the extent of AMPK activation via the eIF4F-PP2A-AMPK axis. Pharmacological inhibition of this axis can overcome the negative control of AMPK signaling by the ERK pathway. This suggests new therapeutic opportunities to disrupt melanoma growth.

cancer biology↗

bioRxiv2021

RNF43 inhibits WNT5A driven signaling and suppresses melanoma invasion

RNF43 is a E3 ubiquitin ligase and known negative regulator of WNT/{beta}-catenin signaling. We demonstrate that RNF43 is also regulator of noncanonical WNT5A-induced signaling in human cells. Analysis of the RNF43 interactome using BioID and immunoprecipitation showed that RNF43 can interact with the core receptor complex components dedicated to the noncanonical Wnt pathway such as ROR1, ROR2, VANGL1 and VANGL2. RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and clathrin-dependent internalization of ROR1 receptor. This activity of RNF43 is physiologically relevant and blocks pro-metastatic WNT5A signaling in melanoma. RNF43 inhibits responses to WNT5A, which results in the suppression of invasive properties of melanoma cells. Furthermore, RNF43 prevented WNT5A-assisted development of resistance to BRAF V600E inhibitor. In line with these findings, RNF43 expression decreases during melanoma progression and RNF43-low patients have worse prognosis. We conclude that RNF43 is a newly discovered negative regulator of WNT5A-mediated biological responses that desensitizes cells to WNT5A.

cancer biology↗