PDE5 expression in human thyroid tumors and effects of PDE5 inhibitors on growth and migration of cancer cells

Abstract

Recent studies have revealed in normal thyroid tissue the presence of the transcript of several phosphodiesterases (PDEs), enzymes responsible for the hydrolysis of cyclic nucleotides. In this work, we analyzed the expression of PDE5 in a series of human papillary thyroid carcinomas (PTCs) presenting or not BRAF V600E mutation and classified according to ATA risk criteria. Furthermore, we tested the effects of two PDE5 inhibitors (sildenafil, tadalafil) against human thyroid cancer cells. PDE5 gene and protein expression were analyzed in two different cohorts of PTCs by real-time PCR using a TaqMan micro-fluid card system and Western blot. MTT and migration assay were used to evaluate the effects of PDE5 inhibitors on proliferation and migration of TPC-1, BCPAP, and 8505C cells. In a first series of 36 PTCs, we found higher expression levels of PDE5A in tumors versus non-tumor (normal) tissues. PTCs with BRAF mutation showed higher levels of mRNA compared with those without mutation. No significant differences were detected between subgroups with low and intermediate ATA risk. Upregulation of PDE5 was also detected in tumor tissue proteins. Similar results were obtained analyzing the second cohort of 50 PTCs. Moreover, all tumor tissues with high PDE5 levels showed reduction of Thyroglobulin, TSH receptor, Thyroperoxidase, and NIS transcripts. In thyroid cancer cells in vitro, sildenafil and tadalafil determined a reduction of proliferation and cellular migration. Our findings demonstrate for the first time an overexpression of PDE5 in PTCs, and the ability of PDE5 inhibitors to block the proliferation of thyroid cancer cells in culture, therefore, suggesting that specific inhibition of PDE5 may be proposed for the treatment of these tumors.

Expression and Function of Phosphodiesterase Type 5 in Human Breast Cancer Cell Lines and Tissues: Implications for Targeted Therapy

“…In the last ten years, various PDE5 inhibitors have been also reported to inhibit growth and induce apoptosis in many cancer cell lines, without affecting normal epithelial cells (12-14, 16, 18, 19). Recently, two reports have suggested a role for PDE5 inhibition in influencing cancer cell motility (17,45). Indeed, tadalafil and sildenafil reduced the capacity of thyroid cancer cells to migrate at lower doses than those used to block proliferation (17).…”

“…Recently, two reports have suggested a role for PDE5 inhibition in influencing cancer cell motility (17,45). Indeed, tadalafil and sildenafil reduced the capacity of thyroid cancer cells to migrate at lower doses than those used to block proliferation (17). Similarly, downregulation of PDE5 in the aggressive human breast cancer cell line MDA-MB-231T resulted in no difference in cell proliferation and reduced motility in vitro and in vivo (45).…”

“…The increased expression of PDE5 in human malignancies coupled with the efficacy and high tolerability profiles of PDE5 inhibitors (i.e., sildenafil and vardenafil) in the treatment of erectile dysfunction and pulmonary hypertension have led to an increased interest in investigating PDE5-targeted drugs in cancer management (14,15). Indeed, several in vitro observations have shown antiproliferative and proapoptotic effects of PDE5 inhibitors in cancer cell lines, as those of the breast (13,14,16,17). Another PDE5 inhibitor, the nonsteroidal anti-inflammatory drug exisulinid, inhibited growth and induced apoptosis in human tumor cells through cGMP elevation and PKG activation (12,18,19).…”

Effect of sildenafil on human aromatase activity: From in vitro structural analysis to catalysis and inhibition in cells

“…Very recently, an overexpression of phosphodiesterase-5 (PDE5) was observed in several cancer tissues and cell lines, including those of the breast and thyroid glands [10,11]. Moreover, sildenafil that is a cyclic guanosine monophosphate (cGMP)-specific PDE5 inhibitor used for the treatment of erectile dysfunction and pulmonary hypertension [12] has attracted the attention of scientists since different studies have reported that this molecule has a synergic effect with some anti-cancer drugs such as doxorubicin in breast cancer cells [13].…”

“…Moreover, sildenafil that is a cyclic guanosine monophosphate (cGMP)-specific PDE5 inhibitor used for the treatment of erectile dysfunction and pulmonary hypertension [12] has attracted the attention of scientists since different studies have reported that this molecule has a synergic effect with some anti-cancer drugs such as doxorubicin in breast cancer cells [13]. More recently, different studies show that sildenafil blocks the proliferation of colorectal [14] and thyroid cancer cells [11].…”