The overall structure of the superfamily of the 3´,5´-cyclic nucleotide phosphodiesterases (PDEs) proteins is highly conserved across species Citation[1]. This is because these enzymes play a very important role in signaling: they regulate the intracellular levels of the secondary messengers cAMP and cGMP Citation[2]. These messengers are ubiquitous molecules that mediate a variety of cellular functions and their intracellular levels are critical for the transduction of cyclic nucleotide signaling. PDEs are divided into 11 families based on structural homology and biochemical features; the various PDEs are coded by 24 genes that produce more than 70 proteins due to extensive (and tissue-specific) gene splicing.
In addition to undergoing extensive splicing, most PDE genes are highly polymorphic; functional polymorphisms are present in both patient and healthy controls groups. In addition, many mutations that are found in association with certain diseases can be observed in both groups, but their frequency differs between patients and controls. This means that PDE variants, mutant or polymorphic, may confer pathogenicity in a genetic background-, tissue- and microenvironment-specific manner.
There are several concrete and even more possible disease associations with PDE genes that have been described. PDE2A seems to be involved in the regulation of aldosterone production in adrenal zona glomerulosa cells and is a candidate gene for hypertension Citation[3]. PDE4B has been implicated in the pathogenesis of schizophrenia Citation[4]. Defects in PDE6 cause an eye disease inherited in an autosomal recessive manner, a form of retinitis pigmentosa Citation[5], and PDE11A polymorphisms have been associated with depression Citation[6].
PDE11A is also the first PDE that was implicated in predisposition to tumors: inactivating PDE11A variants were found to be more frequent among patients with several types of endocrine tumors, including adrenocortical, pituitary and testicular germ-cell tumors Citation[7–9]. More recently, we reported a higher prevalence of PDE11A-inactivating variants among patients with prostate cancer than in healthy controls. Immunohistochemistry showed decreased PDE11A protein expression in prostate cancer tumors with PDE11A sequence changes compared with the ones with the wild-type PDE Citation[10].
Pharmacological exploitation of the diversity of PDEs has led to the discovery of drugs with selective action against specific isoforms. The therapeutic success of PDE5 inhibitors for the treatment of erectile dysfunction was followed by their use in the treatment of heart failure and pulmonary hypertension.
However, the most thoroughly studied PDE family with regards to its interactions with other molecules (e.g., arrestins and the receptor for activated C kinase 1) is PDE4. PDE4 inhibitors may have therapeutic applications in diseases such as asthma, chronic obstructive pulmonary disease and rheumatoid arthritis Citation[5].
More recently, a PDE10A inhibitor has been tested in preclinical research as a new therapeutic approach for the treatment of schizophrenia, disorders of basal ganglia function and other brain defects that are caused by dysfunctional glutamatergic and dopaminergic neurotransmission Citation[11–13]. PDE11A may be a potential target for chemotherapy; several tissues express this enzyme, including lung, breast, colon, adrenal and prostate tissue Citation[14].
Currently, there are conflicting data on the mechanisms through which PDE5A inhibitors affect different tissues. PDE5A inhibitors act through elevation of the intracellular cGMP levels, which in turn downregulates Ca2+ transport and leads to K+ channel activation that results in relaxation of smooth muscle cells. The accumulated cGMP then activates protein kinase (PK)G Citation[15]. Several studies have reported positive effects of PDE5A inhibitors in combination with α1-adrenergic blocker on benign prostatic hyperplasia Citation[16–18]. In addition, studies have demonstrated that PDE5A protein can repress cell proliferation in human cultured breast tumor, colon adenocarcinoma and human prostatic stromal cells lines Citation[19–21]. It appears that the effects of PDE5A inhibitors on cell proliferation are dose- and time-dependent in human cultured prostate stroma cells Citation[21]. These data are in contrast to other results showing that PDE5A may cause downregulation of PKG, which leads to cell proliferation through activation of the MAPKs, enhancement of migration and new vessel growth Citation[22,23]. In addition, higher levels of calcium are shown to activate nitric oxide synthase, thus elevating the intracellular levels of nitric oxide and inducing apoptosis through p53 Citation[24,25]. Moreover, PDE5A inhibitors causing greatly increased concentrations of cGMP can lead to ‘crossover’ stimulation of the cAMP signaling pathway by activating PKA Citation[22,26]. Clearly these data suggest that in order to elucidate the different, sometimes opposing, mechanisms by which PDE5A inhibitors exert their effects in different tissues, more work needs to be carried out both in vitro and in vivo. The issue of cross-interactions also needs to be addressed as most PDE5 inhibitors also inhibit PDE11A, albeit weakly Citation[27–29].
Protein interactions between PDEs and other cAMP- and/or cGMP signaling-related molecules (PKA, PKB, PKC and MAPK) have also been described. PKA interacts with PDEs both directly (i.e., with PDE7) and indirectly, via the A-kinase-anchoring proteins. Understanding the PDEs’ genetic interactions in the prostate is essential. As shown in prior studies, inhibition of cAMP signaling may cause antiproliferative and proapoptotic effects on prostate cancer cells Citation[30,31]. On the other hand, stimulation of PKG in the absence of VEGF leads to Raf-1 activation, and Raf-1 stimulation activates Fyn, which is required for enhanced invasion and increased malignancy potential for both prostate cancer and other cancers Citation[22,32,33].
In conclusion, PDE-modulating drugs may have many potential therapeutic applications; however, better understanding of the function and genetic heterogeneity of PDEs is required. Cancers of endocrine (and other) tissues are particularly good targets of PDE-related drugs, due to their enhanced sensitivity to cAMP and/or cGMP levels.
Acknowledgement
The authors would like to thank Dr Anelia Horvath for her helpful comments and suggestions on this manuscript.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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