Attenuated proliferation and trans-differentiation of prostatic stromal cells indicate suitability of phosphodiesterase type 5 inhibitors for prevention and treatment of benign prostatic hyperplasia.
Benign prostatic hyperplasia (BPH) is characterized by tissue overgrowth and stromal reorganization primarily due to cellular proliferation and fibroblast-to-myofibroblast trans-differentiation. To evaluate the potential of phosphodiesterase type 5 (PDE5) inhibitors like tadalafil for prevention and treatment of BPH, we analyzed the role of the nitric oxide/cyclic GMP (cGMP)/PDE5 pathway for cellular proliferation and TGFbeta1-induced fibroblast-to-myofibroblast trans-differentiation in primary prostate stromal cells. Inhibition by tadalafil of PDE5, which is mainly expressed in the stromal compartment of the prostate, reduced proliferation of primary prostate stromal cells and to a lesser extent of primary prostate basal epithelial cells. Attenuated proliferation due to elevated intracellular cGMP levels was confirmed by inhibition of the cGMP-dependent protein kinase G by its inhibitor KT2358. Moreover, tadalafil strongly attenuated TGFbeta1-induced fibroblast-to-myofibroblast trans-differentiation. The inhibitory effect on trans-differentiation was also observed after small interfering RNA-mediated PDE5 knockdown. As confirmed by the MAPK kinase 1 inhibitor PD98059, this effect was mediated via MAPK kinase 1 signaling. We conclude that BPH patients might benefit from adjuvant therapies with PDE5 inhibitors that inhibit stromal enlargement due to cell proliferation, as well as TGFbeta1-induced trans-differentiation processes.
Zenzmaier
Christoph
C
Institute for Biomedical Aging Research, Austrian Academy of Sciences, Austria.
Sampson
Natalie
N
Pernkopf
Dominik
D
Plas
Eugen
E
Untergasser
Gerold
G
Berger
Peter
P
D002243:Carbolines / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects*; D054338:Cell Transdifferentiation / Q000187:drug effects*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011467:Prostate / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D017154:Stromal Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D000068581:Tadalafil; D016896:Treatment Outcome
D002243:Carbolines; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D034741:RNA, Small Interfering; D000068581:Tadalafil; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP