Androgen Receptor Activation Induces Senescence in Thyroid Cancer Cells

SIMPLE SUMMARY: Thyroid cancer is the most common endocrine malignancy and occurs three times more frequently in women than in men. Further, androgen receptor expression is decreased in thyroid cancer cells. These observations suggest that male hormones may play a role in the prevention of thyroid cancer. We show that androgen stimulation of the androgen receptor inhibits the growth of thyroid cancer cells by inducing a state of senescence, in which cells are not killed, but are unable to multiply. Further work will investigate the ability to use androgens to treat thyroid cancer cells, as well as the possibility of treating and eliminating senescent cells using specific drugs. 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.