cAMP-specific phosphodiesterase 8A and 8B isoforms are differentially expressed in human testis and Leydig cell tumor

Abstract

Cyclic adenosine monophosphate/Protein kinase A (cAMP/PKA) signaling pathway is the master regulator of endocrine tissue function. The level, compartmentalization and amplitude of cAMP response are finely regulated by phosphodiesterases (PDEs). PDE8 is responsible of cAMP hydrolysis and its expression has been characterized in all steroidogenic cell types in rodents including adrenal and Leydig cells in rodents however scarce data are currently available in humans. Here we demonstrate that human Leydig cells express both PDE8A and PDE8B isoforms. Interestingly, we found that the expression of PDE8B but not of PDE8A is increased in transformed Leydig cells (Leydig cell tumors-LCTs) compared to non-tumoral cells. Immunofluorescence analyses further reveals that PDE8A is also highly expressed in specific spermatogenic stages. While the protein is not detected in spermatogonia it accumulates nearby the forming acrosome, in the trans-Golgi apparatus of spermatocytes and spermatids and it follows the fate of this organelle in the later stages translocating to the caudal part of the cell. Taken together our findings suggest that 1) a specific pool(s) of cAMP is/are regulated by PDE8A during spermiogenesis pointing out a possible new role of this PDE8 isoform in key events governing the differentiation and maturation of human sperm and 2) PDE8B can be involved in Leydig cell transformation.

Once upon a Testis: The Tale of Cyclic Nucleotide Phosphodiesterase in Testicular Cancers

“…PDE3A is expressed in the heart, vascular smooth Few reports characterized PDE2A expression in testis. Microarray data regarding the expression of PDE genes in different human tissues reported a high level of PDE2A in the human testis [64], later confirmed by the QuantiGene Bioplex Assay [65] (Table 2). Positive results were obtained in human ejaculated spermatozoa [66] while low expression levels were detected in murine spermatozoa [31] (Table 1).…”

“…A higher frequency of PDE11A sequence variants in patients with large-cell calcifying Sertoli cell tumors was identified, pointing out how PDE11A could be considered a genetic modifying factor for the development of testicular tumors, acting directly on germ cells or indirectly through somatic cells [166]. Recently, we have demonstrated that during Leydig cell neoplastic transformation PDE8B expression levels increased compared to the normal testis, while PDE8A levels were almost comparable between the two sample groups suggesting, for the first time, a potentially pivotal role of PDE8B in LCs dysfunction [65] (Figure 12). functionally inactivating, resulting in reduced PDE activity and increased cAMP levels (Figure 12) [164].…”

“…2023, 24, x FOR PEER REVIEW 8 of 27 acrosome of elongating and maturing spermatids in close proximity to microtubules present in the transitory structure of the manchette indicating that PDE4D mRNA is not efficiently translated at round spermatids stages but it reaches a maximal intensity at steps 18-19 before spermiation [40]. PDE4A, PDE4B and PDE4D have been detected with a similar rate of expression in whole human testis extract [65] (Table 2).…”

“…Three murine and human isoforms have been characterized so far that are transcribed from different promoters, producing three N-terminal variants (PDE5A1, PDE5A2, PDE5A3) [47,90,91] (Figure 5). PDE5A transcripts are widely expressed but high levels have been detected in several sections of the digestive system, lung, platelets, cerebellum, kidney, vascular smooth muscle cells, skeletal and cardiac muscle [92][93][94][95][96][97][98], and several endocrine glands, including testis [47,65,99].…”

“…Moreover, a microarray analysis of phosphodiesterases expression on human tissues showed that PDE8A is expressed at moderate levels in normal testis while PDE8B levels are undetectable. We recently demonstrated that human Leydig cells express both PDE8A and PDE8B isoforms and that PDE8A is also highly expressed in specific spermatogenic stages, suggesting a potentially pivotal role of PDE8A in controlling key events of maturation of human sperm [65] (Table 2).…”