Effects of WNK and NUAK inhibitors on prostate smooth muscle contraction and prostate growth

• Applicant: Professor Dr. Martin Hennenberg
• Subject Area: Reproductive Medicine, Urology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457843581

Voiding symptoms suggestive of benign prostatic hyperplasia (BPH) are characterized by high prevalence, while medical treatment still represents a challenge. Driving factors of voiding symptoms in BPH are an increased prostate smooth muscle tone and benign prostatic growth. Both factors contribute to urethral obstruction/compression, finally resulting in impairments of urinary flow and bladder emptying. Consequently, medical treatment addresses contraction (including α1-adrenoceptor antagonists as the first-line option) or growth (5α-reductase inhibitors). However, available options improve symptoms only partially, and in particular combination therapies are often discontinued due to low tolerability. The limitation of symptom improvement is explained by lacking effects on α1-adrenoceptor-independent contractions, which may keep prostate smooth muscle tone elevated despite application of α1-blockers. Innovative, new targets for future options should consequently inhibit adrenergic and non-adrenergic contractions, as well as proliferation of prostate cells at once.In parallel to α1-adrenoceptors and their partially well known postreceptor signaling patthways, prostate smooth muscle contraction is induced by non-adrenergic receptors and promoted by further intracellular signaling pathways. The latter are partially involved in proliferation of prostate cells. In contrast to previous models, contraction and growth in the hyperplastic prostate are no separate phenomena, but obviously connected with each other. Isoforms of the „with no lysine/K kinases“ (WNKs) are involved in vasocontraction and proliferation of vascular smooth muscle cells. Development of WNK inhibitors, and exploring their effects are topics of high current interest. NUAKs, in turn, are two members of AMP-activated protein kinases. At molecular level, NUAK-mediated regulation of contraction-relevant mechanisms has become increasingly obvious. At functional level, however, they are poorly/hardly understood, apart from a role in proliferation of several cell types. Thus, based on findings from other organs and several cell types, a role of WNKs and NUAKs appears possible for prostate smooth muscle contraction and proliferation of prostate cells, what has been supported by preliminary experiments in the applicant’s lab. The proposed project aims to examine effects of WNK and NUAK inhibitors on adrenergic and non-adrenergic contractions of human prostate tissues, and on proliferation of prostate cells. Silencing of WNK and NUAK expression in cell culture experiments will be performed to validate the their possible involvement in these processes.

• DFG Programme: Research Grants