Androgen Receptor Activation Induces Senescence in Thyroid Cancer Cells

Authors

Anvita Gupta, Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA.
Michelle Carnazza, Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA.
Melanie Jones, Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA.
Zbigniew Darzynkiewicz, Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA.
Dorota Halicka, Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA.
Timmy O'Connell, Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA.
Hong Zhao, Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA.
Sina Dadafarin, Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA.
Edward Shin, Department of Otolaryngology, New York Eye and Ear Infirmary of Mount Sinai, New York, NY 10003, USA.
Monica D. Schwarcz, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA.
Augustine Moscatello, Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA.
Raj K. Tiwari, Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA.
Jan Geliebter, Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY 10595, USA.

Author Type(s)

Faculty

Journal Title

Cancers

Document Type

Article

Publication Date

4-7-2023

Department

Otolaryngology

Second Department

Pathology, Microbiology and Immunology

Abstract

Thyroid cancer (TC) is the most common endocrine malignancy, with an approximately three-fold higher incidence in women. TCGA data indicate that androgen receptor (AR) RNA is significantly downregulated in PTC. In this study, AR-expressing 8505C (anaplastic TC) (84E7) and K1 (papillary TC) cells experienced an 80% decrease in proliferation over 6 days of exposure to physiological levels of 5α-dihydrotestosterone (DHT). In 84E7, continuous AR activation resulted in G1 growth arrest, accompanied by a flattened, vacuolized cell morphology, with enlargement of the cell and the nuclear area, which is indicative of senescence; this was substantiated by an increase in senescence-associated β-galactosidase activity, total RNA and protein content, and reactive oxygen species. Additionally, the expression of tumor suppressor proteins p16, p21, and p27 was significantly increased. A non-inflammatory senescence-associated secretory profile was induced, significantly decreasing inflammatory cytokines and chemokines such as IL-6, IL-8, TNF, RANTES, and MCP-1; this is consistent with the lower incidence of thyroid inflammation and cancer in men. Migration increased six-fold, which is consistent with the clinical observation of increased lymph node metastasis in men. Proteolytic invasion potential was not significantly altered, which is consistent with unchanged MMP/TIMP expression. Our studies provide evidence that the induction of senescence is a novel function of AR activation in thyroid cancer cells, and may underlie the protective role of AR activation in the decreased incidence of TC in men.

Recommended Citation

Gupta, A., Carnazza, M., Jones, M., Darzynkiewicz, Z., Halicka, D., O'Connell, T., Zhao, H., Dadafarin, S., Shin, E., Schwarcz, M. D., Moscatello, A., Tiwari, R. K., & Geliebter, J. (2023). Androgen Receptor Activation Induces Senescence in Thyroid Cancer Cells. Cancers, 15 (8). https://doi.org/10.3390/cancers15082198