title: Protein kinase A (PKA) pathway is functionally linked to androgen receptor (AR) in the progression of prostate cancer.
abstract: OBJECTIVE
  In the present study, we investigated whether the cyclic adenosine monophosphate (cAMP)-activated protein kinase A (PKA) pathway may regulate the expression of AR and prostate-specific antigen (PSA) and whether there is a correlation between the expression of cAMP/PKA-associated genes and androgen receptor (AR) in patients with prostate cancer (CaP).
  
  
  METHODS
  The functional studies were performed in LNCaP and PC3 cell lines. Data on the mRNA expression of sets of genes in human clinical samples, including prostate tissues from organ donors, prostate primary cancer, and metastatic cancer, were extracted from the National Center for Biotechnology Informations Gene Expression Omnibus (GEO) database. Statistical tests were applied.
  
  
  RESULTS
  We showed that elevated levels of cAMP/PKA pathways induced an increased expression of AR and PSA proteins in LNCaP cells in the absence of androgen. A cAMP-associated phosphodiesterase-4 (PDE4) inhibitor, rolipram induced an up-regulation in AR expression, whereas a cAMP enhancer, forskolin increased PSA level without affecting AR expression. Forskolin treatment increased the level of PKA R1α in LNCaP cells, but remarkably inhibited R1α expression in aggressive PC3 cells. In patients with CaP, we found that the expression of genes encoding R1α and phosphodiesterase-4B was statistically significantly lower in the metastatic specimens than that in the primary CaP specimens or in the normal prostate tissues (P<0.01) and was reversely correlated with AR expression. Conversely, AR and PRKAR2B mRNA expressions were significantly higher in metastatic lesions than those in the primary CaP specimens or in the normal prostate tissues (P<0.01).
  
  
  CONCLUSIONS
  Our study revealed a novel mechanism to precisely define the functional and clinical interrelationship between the cAMP/PKA pathway and AR signaling in the development of androgen-independent growth of CaPs and metastasis progression.
authors: Division of Experimental Cancer Research, Department of Laboratory Medicine, Malmö, CRC, Lund University, Malmö, Sweden.
authors: Martuza
authors: M
authors: Sarwar
authors: Division of Experimental Cancer Research, Department of Laboratory Medicine, Malmö, CRC, Lund University, Malmö, Sweden.
authors: Sabina
authors: S
authors: Sandberg
authors: Department of Clinical Sciences, Division of Urologic Research, Skåne University Hospital, Lund University, Malmö, Sweden.
authors: Per-Anders
authors: PA
authors: Abrahamsson
authors: Division of Experimental Cancer Research, Department of Laboratory Medicine, Malmö, CRC, Lund University, Malmö, Sweden. Electronic address: jenny_l.persson@med.lu.se.
authors: Jenny L
authors: JL
authors: Persson
mesh_terms: D045744:Cell Line, Tumor; D005576:Colforsin / Q000737:chemistry; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D020889:Rolipram / Q000737:chemistry; D015398:Signal Transduction
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517355:PDE4A protein, human; D017430:Prostate-Specific Antigen; D020889:Rolipram
keywords: AR; CRPC; CaP; CaP metastasis; Forskolin; GEO; Gene Expression Omnibus; PDE; PKA; Rolipram; cAMP; cAMP/PKA pathways; castration-resistant prostate cancer; cyclic adenosine monophosphate; phosphodiesterase; prostate cancer; protein kinase A