Biology subjects

Santofimia-Castano, P.

Publications and source records attributed to Santofimia-Castano, P..

4 recordsLinked to original sources

bioRxiv2025

The ferroptosis inhibitor NUPR1 coordinates the mitochondrial response to oxidative stress and cell metabolism during COPD pathogenesis in the lung

Chronic obstructive pulmonary disease (COPD) is characterized by chronic injury and oxidative stress leading to progressive lung tissue destruction. Emerging evidence suggests that regulated cell death pathways, particularly ferroptosis, contribute to COPD pathology. We previously identified the stress response protein and known ferroptosis inhibitor nuclear protein 1 (NUPR1) as markedly downregulated in lung tissue from COPD patients. Here, we demonstrate that NUPR1 inhibition exacerbates iron accumulation, enhances lipid peroxidation, impairs mitochondrial function, disrupts cellular metabolism, and increases oxidative stress in lung epithelial cells. Furthermore, Nupr1 knockout mice exhibit mitochondrial abnormalities, increased oxidative damage, and lung tissue changes consistent with COPD pathology. Collectively, our findings establish NUPR1 as a critical regulator of ferroptosis, stress responses, mitochondrial integrity, and metabolic balance in the lung, highlighting its potential contribution to COPD pathogenesis.

cell biology↗

bioRxiv2025

KRAS Inhibition Reverses Chemotherapy Resistance Promoted by Therapy-Induced Senescence-like in Pancreatic Ductal Adenocarcinoma

BackgroundEmerging evidence suggests that chemotherapy can accumulate senescent-like cells within tumor tissues, a phenomenon linked to therapy resistance. The aim of this study is to analyze the senescence-like state of after-treatment persistent cells associated with KRAS mutational status to offer a therapeutic strategy to target these cells in pancreatic ductal adenocarcinoma (PDAC). Experimental DesignThree commercial cell lines and five patient-derived primary cell cultures with different KRAS statuses were studied following gemcitabine treatment. Senescence-like status was assessed using SA-{beta}-gal, together with cell cycle regulators such as p21. Additionally, KRAS mutations were modulated using MRTX1133 and AMG-510, and the signaling pathways ERK and AKT were analyzed and modulated in vitro. Finally, p21 expression, associated with the senescence-like state, on patient outcomes and treatment response was analyzed in publicly available bulk RNA-seq and single-nucleus datasets. ResultsWe observed an overexpression of p21 alongside an increase in SA-{beta}-gal signal in response to gemcitabine treatment, indicating the induction of a senescence-like state. Specific inhibition of KRAS G12D or G12C mutations reduced SA-{beta}-gal signal and sensitized PDAC cells to gemcitabine. Moreover, ERK inhibition but not AKT inhibition decreased SA-{beta}-gal signal. Additionally, we characterized p21 expression levels in relation to patient outcomes and found that they are modulated by treatment. ConclusionsThis dual-targeted therapeutic strategy holds promises for overcoming the challenges posed by KRAS-driven cancers, particularly in addressing the formidable obstacle of pancreatic cancer. Highlights The accumulation of senescent-like cells in tumor tissues because of chemotherapy is linked to treatment resistance, specifically in pancreatic ductal adenocarcinoma (PDAC). Therapy-induced senescence-like in PDAC is influenced by the mutational status of KRAS, affecting the response to chemotherapeutic agents. The expression of the p21 is activated in response to therapy-induced senescence-like, particularly after gemcitabine treatment and is associated with patients outcome. Specifically inhibiting the mutated form of KRAS with small compounds can sensitize PDAC cells to gemcitabine and reduce SA-{beta}-gal signal, acting through the ERK pathway but not the AKT pathway. The study presents a dual-targeted therapeutic strategy that combines KRAS inhibition with cytotoxic agents, potentially improving treatment efficacy and overcoming resistance in KRAS-driven cancers, such as PDAC.

cancer biology↗

bioRxiv2020

The stress-induced protein NUPR1 orchestrates protein translation during ER-stress by interacting with eIF2-a

NUPR1 is a stress response protein overexpressed upon cell injury in virtually all organs including the exocrine pancreas. Despite NUPR1s well established role in the response to cell stress, the molecular and structural machineries triggered by NUPR1 activation remain largely unknown. In this study, we uncover an important role for NUPR1 in participating in the unfolded protein response pathway and the endoplasmic reticulum stress response. Biochemical results, confirmed by ultrastructural morphological observation, revealed alterations in the UPR in acinar cells of germline-deleted NUPR1 murine models, consistent with the inability to restore general protein translation. Bioinformatical analysis of NUPR1 interacting partners showed significant enrichment in translation initiation factors, including eukaryotic initiation factor (eIF) 2. Co-immunoprecipitation and proximity ligation assays both confirmed interaction between NUPR1 and eIF2 and its phosphorylated form (p-eIF2). Our. Moreover, our data also suggest loss of NUPR1 in cells results in maintained eIF2 phosphorylation and evaluation of nascent proteins by (peIF2), and click chemistry revealed that NUPR1-depleted PANC-1 cells displayed a slower post stress protein translational recovery compared to wild-type. Combined, this data proposes a novel role for NUPR1 in the integrated stress response pathway, at least partially through promoting efficient PERK-branch activity and resolution through a unique interaction with eIF2. SignificanceIn the pancreas, NUPR1 is required for a resolution of the ER stress response. During ER stress response, NUPR1 binds both eIF2 allowing for its dephosphorylation and restoration of new protein synthesis. HighlightsBiochemical analysis revealed a general reduction in the protein expression of downstream mediators of the unfolded protein response in the pancreas of mice lacking Nupr1. This finding suggests a novel role for NUPR1 in the UPR/ER stress response. Ultrastructural analysis of pancreata revealed reduced morphological alterations in tunicamycin-treated Nupr1-/- mice compared to Nupr1+/+ mice consistent with a maintained block in general protein translation. Co-immunoprecipitation of tagged NUPR1 confirmed a novel interaction with eIF2. Depletion of NUPR1 prolonged phosphorylation of eIF2, suggesting it may be involved in attenuation of the PERK branch of the UPR. NUPR1-depleted PANC-1 cells displayed a slower recovery of protein translation following UPR activation

cell biology↗

bioRxiv2018

Inactivation of NUPR1 promotes cell death by coupling ER-stress responses with necrosis

Genetic inhibition of NUPR1 induces tumor growth arrest. Inactivation of NUPR1 expression in pancreatic cancer cells results in lower ATP production, higher consumption of glucose with a significant switch from OXPHOS to glycolysis followed by necrotic cell death. Importantly, induction of necrosis is independent of the caspase activity. We demonstrated that NUPR1 inactivation triggers a massive release of Ca2+ from the endoplasmic reticulum (ER) to the cytosol and a strong increase in ROS production by mitochondria with a concomitant relocalization of mitochondria to the vicinity of the ER. In addition, transcriptomic analysis of NUPR1-deficient cells shows the induction of an ER stress which is associated to a decrease in the expression of some ER stress response-associated genes. Indeed, during ER stress induced by the treatment with thapsigargin, brefeldin A or tunicamycin, an increase in the mitochondrial malfunction with higher induction of necrosis was observed in NUPR1-defficent cells. Finally, activation of NUPR1 during acute pancreatitis protects acinar cells of necrosis in mice. Altogether, these data enable us to describe a model in which inactivation of NUPR1 in pancreatic cancer cells results in an ER stress that induces a mitochondrial malfunction, a deficient ATP production and, as consequence, the cell death by necrosis.\n\nHighlightsNUPR1 expression promotes pancreatic cancer development and progression\n\nNUPR1-depletion is a promising therapeutic strategy to be used for treating cancers\n\nNUPR1-depletion induces ER stress, mitochondrial malfunction and a significant switch from OXPHOS to glycolysis followed by necrotic cell death\n\nInactivation of NUPR1 antagonizes cell growth by coupling a defective ER-stress response and a caspase-independent necrosis.

cell biology↗