The constitutive expression of BCL6 sustains the lymphoma phenotype and promotes glioblastoma through transcriptional repression of the DNA damage sensor ATR ( Ranuncolo et al., 2007) and the p53 pathway ( Xu et al., 2017), respectively. BCL6 binds and represses different target genes to drive tumorigenesis in a cell context-dependent manner ( Ci et al., 2009). Increasing evidences indicate that BCL6 plays an oncogenic role in several human hematopoietic malignancies and solid tumors ( Cardenas et al., 2017 Deb et al., 2017 Kawabata et al., 2021). The transcriptional repressor BCL6 has emerged as a critical therapeutic target in diffuse large B-cell lymphomas ( Parekh et al., 2008). While several signaling effectors have been identified as predictive markers, such as ABCA1 ( Koh et al., 2019) and MAST1 ( Jin et al., 2018), in tumor tolerance to genotoxic agents, the majority of these studies lacked either an evaluation of the clinical correlation or an explanation for how these effectors mediate pro-survival signals in the context of genotoxic stress. Chemoresistance occurs due to complex reasons, such as an increased DNA damage repair capacity, activation of pro-survival pathways, and defects in caspase activity ( Bernard et al., 2019 Poth et al., 2010 Zhang et al., 2021). Despite initial therapeutic success, intrinsic resistance or rapid adaptive resistance in cancer cells is a major hurdle, hampering the clinical efficacy of these agents ( Liang et al., 2019 Stebbing et al., 2018). topoisomerase II inhibitors, cisplatin, and carboplatin) that introduce DNA damage lesions, devastate genomic integrity and activate pro-apoptotic pathways, are employed as the standard first-line treatment for a wide array of solid malignancies. Conventional genotoxic chemotherapy (e.g.
Genome instability is the major hallmark of chronic proliferating tumors ( Hanahan, 2022). Our findings highlight the importance of BCL6 signaling in conquering solid tumor tolerance to genotoxic stress, further establishing a rationale for a combined approach with genotoxic agents and BCL6-targeted therapy. Accordingly, targeted inhibition of BCL6 remarkably enhanced etoposide-triggered DNA damage and apoptosis both in vitro and in vivo. The increased expression of BCL6 further repressed the tumor suppressor PTEN and consequently enabled resistant cancer cell survival.
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Our results further revealed that the activation of interferon/signal transducer and activator of transcription 1 axis directly upregulated BCL6 expression. Mechanistically, we discovered that treatment with the genotoxic agent etoposide led to the transcriptional reprogramming of multiple pro-inflammatory cytokines, among which the interferon-α and interferon-γ responses were substantially enriched in resistant cells. Multiple genotoxic agents promoted BCL6 transactivation, which was positively correlated with a weakened therapeutic efficacy and a worse clinical outcome. Here, we report that the oncoprotein B cell lymphoma 6 (BCL6) is a core component that confers solid tumor adaptive resistance to genotoxic stress. Unfortunately, the clinical benefits are often countered by a rapid tumor adaptive response. “That she can be in this position for the rest of her life.Genotoxic agents remain the mainstay of cancer treatment. “They keep saying it’s irreversible,” he said. “Mount Sinai doesn’t comment on pending litigation, but we believe the claim is without merit,” she said.ĭoctors at Mount Sinai have not offered the family much hope, Fen said. Mount Sinai spokeswoman Lucia Lee declined to comment on the situation, but noted that the case is scheduled to go before a judge on Aug. “The physician who spoke with the family afterwards apologized for ‘not being fully prepared’ to deal with the possible consequences, and for ‘not having adequate blood available,'” the court documents state. To make matters worse, Fen said staff was not fully prepared for the procedure. The punctured vein caused internal bleeding, and attempts to repair the damage led to cardiac arrest and a loss of oxygen to her brain for more than 10 minutes, the family claims. It’s not supposed to go through the vein,” Fen explained. “This is when the serious problem began,” the court petition states. In May, the original catheter was removed and a new one inserted. The procedure involved inserting a “large-caliber catheter … deep into Jing’s internal jugular vein,” the legal documents claim.
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