Androgen Receptor Activation Induces Senescence in Thyroid Cancer Cells

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.

Cellular senescence of granulosa cells in the pathogenesis of polycystic ovary syndrome

“…Local hyperandrogenism in PCOS may directly induce the cellular senescence of GCs. It has been reported that androgen receptor activation is linked to the induction of cellular senescence in some cancer cells, including thyroid ( Gupta et al , 2023 ) and prostate ( Mirochnik et al , 2012 ) cancer cells. Alternatively, hyperandrogenism may induce the senescence of GCs via the activation of ER stress.…”

Serum sex hormones correlate with pathological features of papillary thyroid cancer

“…Recent studies have shown that androgen-AR overexpression inhibits the migratory activity and invasive behavior of PTC cells [13], as well as the expression of programmed death receptor ligand 1 (PD-L1) in in vitro studies [8]. Activation of AR induces senescence of PTC cells [7]. Dihydrotestosterone (DHT) induces G1 arrest in androgen-responsive thyroid cancer cells [20].…”

“…Previous studies have identi ed estrogen receptors, androgen receptors, prolactin receptors, and progesterone receptors expressed in PTC lesions [4,5]. It is now believed that estrogens can regulate the development of PTC through genomic or non-genomic effect [6], while androgens have been suggested to inhibit the progression of PTC in recent studies [7,8]. However, the results of these studies are mainly based on in vitro cellular experiments or animal experiments and fail to have su cient evidence for clinical studies.…”

Serum sex hormones correlate with pathological features of papillary thyroid cancer

“…Recent studies have shown that androgen-AR overexpression inhibits the migratory activity and invasive behavior of PTC cells [ 13 ], as well as the expression of programmed death receptor ligand 1 (PD-L1) in in vitro studies [ 8 ]. Activation of AR induces senescence of PTC cells [ 7 ]. Dihydrotestosterone (DHT) induces G1 arrest in androgen-responsive thyroid cancer cells [ 19 ].…”

“…Previous studies have identified estrogen receptors, androgen receptors, prolactin receptors, and progesterone receptors expressed in PTC lesions [ 4 , 5 ]. It is now believed that estrogens can regulate the development of PTC through genomic or non-genomic effect [ 6 ], while androgens have been suggested to inhibit the progression of PTC in recent studies [ 7 , 8 ]. These findings suggest that sex hormones may provide new clinical strategies for papillary thyroid cancer, such as prediction of diagnosis, endocrine therapy, and assessment of prognostic risk, as in breast cancer and prostate cancer.…”