A comprehensive analysis of immunogenic cell death and its key gene HSP90AA1 in bladder cancer

Background Bladder cancer (BLCA) is defined as a type of urinary cancer with high incidence and lack of specific biomarkers and drug targets. Immunogenic cell death (ICD) has been classified as a regulated type of cell death. Growing evidence suggested that ICD can reshape the tumor immune microenvironment, which may contribute to the development of immunotherapy strategies. The aim of this study was to reveal the specific mechanism of ICD in bladder cancer and to further predict the prognostic immunotherapy outcomes. Methods By consensus clustering analysis, bladder cancer patients in TCGA database were divided into different ICD subtypes. Additionally, we developed an ICD-scoring system and constructed the ICD score-based risk signature and nomogram to better characterize patients. Furthermore, we carried out a series of experiments to verify the relevant findings. Results Based on the transcriptome expression levels of ICD-related genes, a total of 403 BLCA patients in the TCGA database were divided into two subgroups with different ICD molecular patterns by consensus cluster analysis. These subgroups showed different clinicopathological features, survival outcomes, tumor microenvironment (TME) characteristics, immune-related scores, and treatment response. Moreover, the established prediction model and ICD score can effectively distinguish high risk/score patients from low risk/score patients, which has excellent predictive value. Finally, we found that the key gene HSP90AA1 was highly expressed in the high-ICD score group and in bladder cancer tissues, and was confirmed to be associated with the proliferation of bladder cancer cells (AU)

Interplay between HSP90 and Nrf2 pathways in diabetes-associated atherosclerosis / Interacción entre las vías HSP90 y Nrf2 en la aterosclerosis asociada a diabetes

Introduction: Oxidative stress and inflammation are determinant processes in the development of diabetic vascular complications. Heat shock protein 90 (HSP90) overexpression in atherosclerotic plaques plays a role in sustaining inflammatory mechanisms, and its specific inhibition prevents atherosclerosis. The present work investigates, in a mouse model of diabetes-driven atherosclerosis, whether atheroprotection by pharmacological HSP90 inhibition is accomplished by bolstering antioxidant defense mechanisms headed by nuclear factor erythroid-derived 2-like 2 (Nrf2). Methods: Streptozotocin-induced diabetic apolipoprotein E-deficient mice were randomized to receive vehicle or HSP90 inhibitor (17-dimethylaminoethylamino-17-demethoxygeldanamycin, 4mg/kg) for 10 weeks. Aortic root sections were analyzed for plaque size and composition, transcription factor activity, and expression of inflammatory and antioxidant markers. In vitro studies were performed in murine macrophages cultured under hyperglycemic conditions. Results: Treatment with HSP90 inhibitor promoted the activation of Nrf2 in the aortic tissue of diabetic mice (predominantly localized in macrophages and smooth muscle cells) and also in cultured cells. Nrf2 induction was associated with a concomitant inhibition of nuclear factor-κB (NF-κB) in atherosclerotic plaques, thus resulting in a significant reduction in lesion size and inflammatory component (leukocytes and cytokines). Furthermore, atheroprotection by HSP90 inhibition was linked to the induction of cytoprotective HSP70, antioxidant enzymes (heme oxygenase-1, superoxide dismutase and catalase) and autophagy machinery (LC3 and p62/SQSTM1) in aortic tissue. Conclusion: HSP90 inhibition protects from atherosclerosis in experimental diabetes through the induction of Nrf2-dependent cytoprotective mechanisms, reinforcing its therapeutic potential

Introducción: Estrés oxidativo e inflamación son procesos clave en las complicaciones vasculares de la diabetes. La expresión de heat shock protein 90 (HSP90) en placas ateroscleróticas prolonga la inflamación, y su inhibición previene la aterosclerosis. Este trabajo investiga, en un modelo de aterosclerosis asociada a diabetes, si el efecto ateroprotector de la inhibición farmacológica de HSP90 está mediado por la inducción de mecanismos de defensa antioxidante dependientes del factor de transcripción nuclear factor erythroid-derived 2-like 2 (Nrf2). Métodos: Ratones deficientes en apolipoproteína E con diabetes por estreptozotocina se trataron durante 10 semanas con el inhibidor de HSP90 (17-dimetilaminoetilamino-demetoxigeldanamicina, 4mg/kg). Analizamos tamaño/composición de las placas, factores de transcripción y marcadores inflamatorios y antioxidantes. In vitro estudiamos macrófagos murinos bajo condiciones de hiperglucemia. Resultados: El inhibidor de HSP90 indujo activación de Nrf2 en aorta de ratones diabéticos (localizado en macrófagos y células de músculo liso) y en células en cultivo. La activación de Nrf2 junto con la inhibición de nuclear factor-κB (NF-κB) en las placas ateroscleróticas resultó en una reducción significativa del tamaño de la lesión y del componente inflamatorio (leucocitos y citocinas). Este efecto ateroprotector se vinculó con un aumento de la proteína citoprotectora HSP70, enzimas antioxidantes (hemoxigenasa-1, superóxido dismutasa y catalasa) y genes de autofagia (LC3 y p62/SQSTM1) en aorta de ratones tratados con el inhibidor de HSP90. Conclusión: La inhibición de HSP90 protege del desarrollo de aterosclerosis en la diabetes experimental a través de la inducción de mecanismos citoprotectores dependientes de Nrf2, lo que refuerza su potencial terapéutico

Inhibidores de HSP90 como futura estrategia terapéutica en la aterosclerosis asociada a diabetes / HSP90 inhibitors as a future therapeutic strategy in diabetes-driven atherosclerosis

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Expresión de Heat Shock Protein-90 (HSP-90) como factor predictor de la respuesta a radioterapia en pacientes con tumores de cabeza y cuello / HSP-90 expression as a predictor of response to radiotherapy in head and neck cancer patients

Introducción y objetivos: La HSP-90 es una proteína intracelular que protege la célula en situaciones de estrés ambiental. El objetivo de este estudio es valorar si la sobreexpresión de alguna de las isoformas de HSP-90 confiere resistencia a la radioterapia en una muestra de tumores de cabeza y cuello. Métodos: Se incluyeron en el estudio 87 pacientes con tumores de cavidad oral, orofaringe, laringe e hipofaringe. En muestras de biopsia pretratamiento se analizaron mediante PCR en tiempo real la expresión de las isoformas de HSP-90. Se utilizaron árboles de decisión para estudiar la relación entre el nivel de expresión de HSP-90 y la recidiva local del tumor. Resultados: La expresión de la isoforma citosólica inducible (HSP90AA) permitió definir 2 grupos con diferentes índices de recidiva local. El grupo con expresión baja presentó un 21,9% de recidivas frente al 38,2% del grupo con expresión alta. Las curvas de supervivencia muestran diferencias en el tiempo libre de recidiva local entre ambos grupos, aunque estas diferencias no alcanzaron significación estadística. Conclusiones: La respuesta de los tumores de cabeza y cuello a la radioterapia parece relacionada con la expresión de HSP-90. Este resultado podría ser de utilidad en la selección de tratamientos en este grupo de pacientes (AU)

Introduction and objectives: HSP-90 is an intracellular protein that protects the cell from environmental stress situations. The overexpression of HSP-90 isoforms could serve as a mechanism of resistance to radiotherapy for tumour cells. We studied this effect in a sample of head and neck tumours. Methods: We included 87 patients diagnosed with oral cavity, oropharynx, larynx and hypopharynx tumours. We studied the expression of the HSP-90 isoforms by real-time PCR on pre-treatment biopsy samples. We analysed the relationship between HSP-90 expression levels and local relapse of the tumour with CRT decision trees. Results: The expression levels of the inducible citosolic isoform (HSP90AA) allowed the definition of 2 groups of patients with different rates of local relapse. The group with a low expression level showed a 2.9% local relapse rate, while the group with a high expression level showed a 38.2% rate. Survival curves showed differences in time to local relapse for both groups of patients. These differences did not reach statistical significance. Conclusions: Radiotherapy response was related to expression levels of HSP-90 in a sample of head and neck cancer patients. This result could prove useful in the selection of treatments for this group of patients (AU)