Targeting androgen receptor as a novel radiosensitizing therapy to improve long-term survival and anti-tumor immunity in glioblastoma via TGF-β/Smad3 Axis reprogramming.
11 affiliations
- 1Department of Radiation Oncology, Mayo Clinic Arizona, Phoenix, AZ, USA.
- 2Department of Radiation Oncology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
- 3School of Biological Sciences, University of Nebraska - Lincoln, Lincoln, NE, USA.
- 4Department of Pathology, University of Nebraska Medical Center, Omaha, NE, USA.
- 5Department of Radiation Oncology, United Hospital of Fujian, Fuzhou, Fujian, P.R. China.
- 6Center for Radiological Research, College of Physicians and Surgeons; Columbia University, New York, New York, NY, USA.
- 7Department of Radiation Oncology, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, New York, NY, USA.
- 8Department of Biomedical Engineering, Huck Life Science Institute, Pennsylvania State University, University Park, PA, USA.
- 9Department of Neurosurgery, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
- 10Department of Radiation Oncology, Mayo Clinic Arizona, Phoenix, AZ, USA. [email protected].
- 11Department of Radiation Oncology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. [email protected].
Abstract
Glioblastoma (GBM) remains the most aggressive primary adult brain cancer with limited therapeutic options. Our prior research demonstrated that androgen receptor antagonists (ARAs) enhance survival in GBM mouse models by preferentially suppressing glioma stem cells. This study investigates the potential of ARAs as radiosensitizers in combination with radiotherapy (RT). Combined effects of ARAs and RT were evaluated using an orthotopic GBM mouse model. RNA-Seq and TCGA analyses delineated AR-associated regulatory networks, while integrated cellular and molecular approaches utilizing human and mouse GBM cell lines, as well as in patient-derived primary high-grade glioma cultures, interrogated signaling and immune paradigms. ARA treatment induced G2/M cell cycle arrest, apoptosis, and downregulated DNA repair genes, with AR expression correlating with the DNA repair and TGF-β pathway. In both immortalized GBM cell lines and primary high-grade glioma cultured cells, ARAs in combination with RT showed only a modest enhancement of radiosensitivity. However, in an orthotopic GBM mouse model, ARA + RT demonstrated a strong synergy, achieving 100% long-term survival, compared to less than 50% with ARA alone and 0% with RT alone. Mechanistically, ARA modulated the TGF-β pathway, durably switching from Smad3 linker to c-terminal phosphorylation (pSmad3C) and inhibiting the LIF/STAT3 axis. Distinct TGF-βs ligand expression patterns were observed in ARA-treated GBM cells. A protein-protein interaction noted between AR and pSmad3, which was disrupted following ARA treatment, leading to elevated protein levels and nuclear localization of pSmad3C (S423/425), indicating normalization/activation of the TGF-β/pSmad3C-dependent anti-tumorigenic cascade. Comprehensive analyses in GBM cell lines and mouse model tissues demonstrated pathway reprogramming characterized by elevated TGF-β2 and increased pSmad3C. Rescue experiments using a TGFβRII degrader with ARA abolished pSmad3C phosphorylation, confirming the functional significance of TGFβRII/pSmad3C axis. Tissue analysis revealed immune activation in the tumor microenvironment, while peripheral blood and spleen showed systemic immune responses following ARA + RT. Our study provides novel insights into how ARAs enhance RT efficacy through immunomodulation involving TGF-β/pSmad3C cascade, offering therapeutic implications in GBM.
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BibTeX
@article{kaushal2026targeting,
title = {{Targeting androgen receptor as a novel radiosensitizing therapy to improve long-term survival and anti-tumor immunity in glioblastoma via TGF-β/Smad3 Axis reprogramming.}},
author = {Jyoti B Kaushal and Nan Zhao and Rubayat Khan and Kan Liu and Chi Zhang and Fei Wang and Jie Chen and Bingjie Guan and Shuo Wang and Tom K Hei and Tony J C Wang and Yuguo Lei and Michele R Aizenberg and Chi Lin and Chi Zhang},
journal = {Cell death discovery},
year = {2026},
month = jul,
doi = {10.1038/s41420-026-03259-9},
url = {https://europepmc.org/article/MED/42901889},
note = {CC BY},
}
RIS
TY - JOUR
TI - Targeting androgen receptor as a novel radiosensitizing therapy to improve long-term survival and anti-tumor immunity in glioblastoma via TGF-β/Smad3 Axis reprogramming.
AU - Jyoti B Kaushal
AU - Nan Zhao
AU - Rubayat Khan
AU - Kan Liu
AU - Chi Zhang
AU - Fei Wang
AU - Jie Chen
AU - Bingjie Guan
AU - Shuo Wang
AU - Tom K Hei
AU - Tony J C Wang
AU - Yuguo Lei
AU - Michele R Aizenberg
AU - Chi Lin
AU - Chi Zhang
PY - 2026
DA - 2026/07/01
JO - Cell death discovery
DO - 10.1038/s41420-026-03259-9
UR - https://europepmc.org/article/MED/42901889
AB - Glioblastoma (GBM) remains the most aggressive primary adult brain cancer with limited therapeutic options. Our prior research demonstrated that androgen receptor antagonists (ARAs) enhance survival in GBM mouse models by preferentially suppressing glioma stem cells. This study investigates the potential of ARAs as radiosensitizers in combination with radiotherapy (RT). Combined effects of ARAs and RT were evaluated using an orthotopic GBM mouse model. RNA-Seq and TCGA analyses delineated AR-associated regulatory networks, while integrated cellular and molecular approaches utilizing human and mouse GBM cell lines, as well as in patient-derived primary high-grade glioma cultures, interrogated signaling and immune paradigms. ARA treatment induced G2/M cell cycle arrest, apoptosis, and downregulated DNA repair genes, with AR expression correlating with the DNA repair and TGF-β pathway. In both immortalized GBM cell lines and primary high-grade glioma cultured cells, ARAs in combination with RT showed only a modest enhancement of radiosensitivity. However, in an orthotopic GBM mouse model, ARA + RT demonstrated a strong synergy, achieving 100% long-term survival, compared to less than 50% with ARA alone and 0% with RT alone. Mechanistically, ARA modulated the TGF-β pathway, durably switching from Smad3 linker to c-terminal phosphorylation (pSmad3C) and inhibiting the LIF/STAT3 axis. Distinct TGF-βs ligand expression patterns were observed in ARA-treated GBM cells. A protein-protein interaction noted between AR and pSmad3, which was disrupted following ARA treatment, leading to elevated protein levels and nuclear localization of pSmad3C (S423/425), indicating normalization/activation of the TGF-β/pSmad3C-dependent anti-tumorigenic cascade. Comprehensive analyses in GBM cell lines and mouse model tissues demonstrated pathway reprogramming characterized by elevated TGF-β2 and increased pSmad3C. Rescue experiments using a TGFβRII degrader with ARA abolished pSmad3C phosphorylation, confirming the functional significance of TGFβRII/pSmad3C axis. Tissue analysis revealed immune activation in the tumor microenvironment, while peripheral blood and spleen showed systemic immune responses following ARA + RT. Our study provides novel insights into how ARAs enhance RT efficacy through immunomodulation involving TGF-β/pSmad3C cascade, offering therapeutic implications in GBM.
SN - 2058-7716
ER -