| Title | Authors | Year |
|---|---|---|
| Abstract A037: Coordinated activity between AR-V7 and glucocorticoid receptor drives resistance to androgen receptor signaling inhibition | Zhang et al. | 2025 |
Summary
Androgen blockade triggers a systemic stress response that elevates cortisol and drives glucocorticoid receptor (NR3C1) overactivation. In prostate cells, the androgen receptor splice variant AR-V7, which lacks a ligand-binding domain, heterodimerizes with NR3C1 to reconstitute a hybrid transcriptional program. This AR-V7–GR complex binds GRE/ARE hybrid DNA elements, reinstating transcription of growth and survival genes even in the absence of androgen signaling.
The resulting transcriptional landscape mirrors the neuronal stress response: heightened excitatory output through NR3C1, elevated calcium handling, and oxidative strain. Over time, the same compensatory hypermethylation seen in neurons emerges at NR3C1 regulatory regions to limit excessive throughput.
Key Molecular Players
- AR-V7: Ligand-independent androgen receptor splice variant that maintains constitutive nuclear activity.
- NR3C1 (GR): Glucocorticoid receptor activated by cortisol, partnering with AR-V7 to maintain signaling under blockade.
- FKBP5: Chaperone and feedback modulator; stabilizes GR/AR complexes and mediates stress sensitivity.
- SGK1 and TSC22D3 (GILZ): Promote survival, ionic balance, and redox adaptation.
- DUSP1: Deactivates MAPK, buffering stress response.
- Surface receptors induced: EGFR, FGFR1, IL6R, ADRB2, ENaC (SCNN1A), NKCC1 (SLC12A2), ZIP6 (SLC39A6), ITGB1, CD44.
Surface Remodeling Effects
- Growth Factor Receptors: EGFR, FGFR1, and IGF1R are upregulated, maintaining PI3K-AKT and MAPK signaling.
- Cytokine and Stress Receptors: IL6R and TNFRSF12A activate STAT3 and NF-κB, perpetuating inflammatory growth signaling.
- Ion Transporters and Channels: ENaC, NKCC1, and ZIP6 increase ionic excitability and redox buffering, paralleling NMDA-driven calcium influx in neurons.
- Adrenergic Receptors: ADRB2 and purinergic P2RX4 amplify cAMP and Ca²⁺ signaling, increasing stress responsiveness.
- Adhesion Molecules: ITGB1 and CD44 promote migration and mechanical resilience, favoring metastasis.
Pathophysiological Parallels
| Cancer Cell Context | Neuronal Context |
|---|---|
| AR-V7–GR maintains proliferation under androgen blockade | NR3C1 activation maintains excitatory signaling under stress |
| EGFR/IL6R/ADRB2 surface expression sustains Ca²⁺ and ROS signaling | NMDA/AMPA upregulation sustains Ca²⁺ and ROS signaling |
| Chronic GR activation leads to NR3C1 hypermethylation | Chronic GR activation leads to NR3C1 hypermethylation |
| Result: Therapy resistance and survival | Result: Excitotoxic injury and neurodegeneration |
Mechanistic Flow
- Androgen Blockade → Cortisol Rise → GR Overactivation
- AR-V7 Expression → GR Recruitment → GRE/ARE Activation
- Transcription of FKBP5, SGK1, GILZ → Cellular Survival
- Surface Remodeling → EGFR / IL6R / ADRB2 / ENaC Upregulation
- Sustained Calcium and ROS Throughput → NR3C1 Hypermethylation
Conceptual Integration
The AR-V7–GR axis represents a somatic mirror of neuronal excitotoxic adaptation.
Under stress (or therapy blockade), cells reroute control through NR3C1 to maintain throughput. The result is transcriptional excitability that preserves short-term function at long-term metabolic cost. This is a unifying principle in our model: stress signaling through NR3C1 universally amplifies receptor density, calcium flow, and ROS production, whether the endpoint is proliferation or neurodegeneration.