INVESTIGADORES
VAZQUEZ Elba Susana
congresos y reuniones científicas
Título:
HO-1 interactors in prostate cancer: role of MX1 in pro-death endoplasmic reticulum stress
Autor/es:
SANCHIS, PABLO A; ORTIZ EMILIANO GERMAN; BIZZOTO, JUAN; LAGE VICKERS, SOFIA; LABANCA ESTEFANIA; ANSELMINO NICOLAS; NAVONE NORA; COTIGNOLA JAVIER; VAZQUEZ ELBA; GUERON GERALDINE
Reunión:
Congreso; Prostate Cancer Foundation Scientific Retreat 2020; 2020
Resumen:
Prostate cancer (PCa) is the second leading cause of cancer death in men worldwide. Androgen ablation is the most effective way of halting PCa progression, but given sufficient time, tumor growth resumes in most cases, and the disease becomes ?castration resistant.? The inflammatory tumor microenvironment is a fertile niche that releases reactive oxygen species, which accelerate the malignant transformation. Heme oxygenase 1 (HO-1), represents an essential event in cellular responses to pro-oxidative and pro-inflammatory insults. We previously reported that HO-1 had a strong anti-tumoral effect in vivo and in vitro, ascertaining it as a logical target for intervention therapy in PCa and undertook an in-depth proteomics study to build the HO-1 interactome in PCa.In this work, we addressed the biological significance of HO-1 interactors through a bioinformatics approach, mining open-access PCa datasets. HO-1 interactors were clustered into three groups according to their expression profile in PCa patients. We carried out an RNA-Seq analysis to compare gene expression profiles between PCa cells genetically overexpressing HO-1 and their respective controls, to evaluate the ability of HO-1 in regulating the expression at the transcriptional level of the proteins included in these clusters. We focused on Myxovirus resistance gene (MX1), as: (1) it was significantly upregulated under HO-1 induction; (2) it was the most consistently downregulated gene in PCa vs. normal prostate; (3) its loss was associated with decreased relapse-free survival in PCa; and (4) there was a significant positive correlation between MX1 and HMOX1 in PCa patients.Next, considering that HO-1 is inducible by inflammatory and stress conditions and that is anchored to the endoplasmic reticulum (ER), we analyzed MX1 expression levels in response to ER stress (ERS), using thapsigargin. Results showed a significant increase of mRNA levels for MX1 under ERS, as well as an upregulation of known markers of this process: HSPA5, DDIT3 and XBP1. Conversely, MX1 silencing reversed these effects. Further, we assessed ERS effect on apoptosis and autophagy. Results showed that, under ERS, apoptosis and autophagy significantly increased in PCa.Further bioinformatics analysis revealed that an increase in the expression of MX1, HMOX1 and ERS genes , reduced the risk of biochemical relapse in patients with PCa that underwent radical prostatectomy.The results of this study evidence that MX1, a novel HO-1 interactor, could drive the ERS balance towards pro-death events in malignant prostatic pathology, making it a promising target for the development of new therapies for PCa. Therefore, drugs that could induce MX1 might be promising therapeutic tools to provide more specific antitumor activity and less toxicity than other treatments.