AI Article Synopsis
- The study investigates the challenge of drug resistance in prostate cancer related to androgen receptor signaling inhibitors (ARSI), highlighting the role of SOX2 overexpression in this resistance.
- Researchers discovered that the gene NR3C1, which encodes the glucocorticoid receptor (GR), is a target of SOX2 and helps regulate its expression.
- By targeting WEE1 kinase in combination with ARSI or GR modulation, the treatment re-sensitized SOX2-positive prostate cancer cells and slowed tumor growth in models, suggesting a potential strategy to overcome resistance.
Article Abstract
The development of androgen receptor signaling inhibitor (ARSI) drug resistance in prostate cancer (PC) remains therapeutically challenging. Our group has described the role of sex determining region Y-box 2 (SOX2) overexpression in ARSI-resistant PC. Continuing this work, we report that NR3C1, the gene encoding glucocorticoid receptor (GR), is a novel SOX2 target in PC, positively regulating its expression. Similar to ARSI treatment, SOX2-positive PC cells are insensitive to GR signaling inhibition using a GR modulating therapy. To understand SOX2-mediated nuclear hormone receptor signaling inhibitor (NHRSI) insensitivity, we performed RNA-seq in SOX2-positive and -negative PC cells following NHRSI treatment. RNA-seq prioritized differentially regulated genes mediating the cell cycle, including G2 checkpoint WEE1 Kinase (WEE1) and cyclin-dependent kinase 1 (CDK1). Additionally, WEE1 and CDK1 were differentially expressed in PC patient tumors dichotomized by high vs low SOX2 gene expression. Importantly, pharmacological targeting of WEE1 (WEE1i) in combination with an ARSI or GR modulator re-sensitizes SOX2-positive PC cells to nuclear hormone receptor signaling inhibition in vitro, and WEE1i combined with ARSI significantly slowed tumor growth in vivo. Collectively, our data suggest SOX2 predicts NHRSI resistance, and simultaneously indicates the addition of WEE1i to improve therapeutic efficacy of NHRSIs in SOX2-positive PC.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.canlet.2023.216209 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
A divergent two-domain structure of the anti-Müllerian hormone prodomain.
Proc Natl Acad Sci U S A
January 2025
Department of Molecular & Cellular Biosciences, University of Cincinnati, Cincinnati, OH 45267.
TGFβ family ligands are synthesized as precursors consisting of an N-terminal prodomain and C-terminal growth factor (GF) signaling domain. After proteolytic processing, the prodomain typically remains noncovalently associated with the GF, sometimes forming a high-affinity latent procomplex that requires activation. For the TGFβ family ligand anti-Müllerian hormone (AMH), the prodomain maintains a high-affinity interaction with its GF that does not render it latent.
View Article and Find Full Text PDFThe Primary Cilia are Associated with the Axon Initial Segment in Neurons.
Adv Sci (Weinh)
January 2025
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China.
The primary cilia serve as pivotal mediators of environmental signals and play crucial roles in neuronal responses. Disruption of ciliary function has been implicated in neuronal circuit disorders and aberrant neuronal excitability. However, the precise mechanisms remain elusive.
View Article and Find Full Text PDFIP3 receptor depletion in a spontaneous canine model of Charcot-Marie-Tooth disease 1J with amelogenesis imperfecta.
PLoS Genet
January 2025
Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
Inositol 1,4,5-trisphosphate receptors (IP3R) mediate Ca2+ release from intracellular stores, contributing to complex regulation of numerous physiological responses. The involvement of the three IP3R genes (ITPR1, ITPR2 and ITPR3) in inherited human diseases has started to shed light on the essential roles of each receptor in different human tissues and cell types. Variants in the ITPR3 gene, which encodes IP3R3, have recently been found to cause demyelinating sensorimotor Charcot-Marie-Tooth neuropathy type 1J (CMT1J).
View Article and Find Full Text PDFCalcium-mediated mitochondrial fission and mitophagy drive glycolysis to facilitate arterivirus proliferation.
PLoS Pathog
January 2025
Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.
Mitochondria, recognized as the "powerhouse" of cells, play a vital role in generating cellular energy through dynamic processes such as fission and fusion. Viruses have evolved mechanisms to hijack mitochondrial function for their survival and proliferation. Here, we report that infection with the swine arterivirus porcine reproductive and respiratory syndrome virus (PRRSV), manipulates mitochondria calcium ions (Ca2+) to induce mitochondrial fission and mitophagy, thereby reprogramming cellular energy metabolism to facilitate its own replication.
View Article and Find Full Text PDFPHIStruct: Improving phage-host interaction prediction at low sequence similarity settings using structure-aware protein embeddings.
Bioinformatics
January 2025
Bioinformatics Lab, Advanced Research Institute for Informatics, Computing and Networking, De La Salle University, Manila, 1004, Philippines.
Motivation: Recent computational approaches for predicting phage-host interaction have explored the use of sequence-only protein language models to produce embeddings of phage proteins without manual feature engineering. However, these embeddings do not directly capture protein structure information and structure-informed signals related to host specificity.
Results: We present PHIStruct, a multilayer perceptron that takes in structure-aware embeddings of receptor-binding proteins, generated via the structure-aware protein language model SaProt, and then predicts the host from among the ESKAPEE genera.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!