Quinazoline-based alpha 1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-beta signalling and I kappa B alpha induction.
Previous studies documented the ability of quinazoline-based alpha1-adrenoceptor antagonists to induce apoptosis in prostate cancer cells via an alpha 1-adrenoceptor-independent mechanism. In this study we investigated the molecular events initiating this apoptotic effect. Since transforming growth factor-beta 1 (TGF-beta 1) mediates prostate epithelial cell apoptosis, we hypothesised that the activation of the TGF-beta 1 pathway underlies the quinazoline-based apoptotic effect in prostate cancer cells. Treatment of the androgen-independent human prostate cancer cells PC-3 with doxazosin resulted in a strong caspase-3 activation within 24 h, whereas tamsulosin, a sulphonamide-based alpha 1-adrenoceptor antagonist, had no significant apoptotic effect against prostate cancer cells. To identify the molecular components involved in this quinazoline-mediated apoptosis, cDNA microarray analysis of PC-3 prostate cancer cells treated with doxazosin (3 h) was performed. Induced expression of several genes was observed including p21(WAF-1) and I kappa B alpha (inhibitor of NF-kappa B alpha). Relative quantitative reverse transcription-polymerase chain reaction analysis revealed induction of several TGF-beta1 signalling effectors: Induction of mRNA for Smad4 and the TGF-beta1-regulated apoptosis-inducing transcription factor TGF-beta1-inducible early gene (TIEG1) was detected within the first 6 h of doxazosin treatment. Upregulation of I kappa B alpha at both the mRNA and protein level was also detected after 6 h of treatment. Furthermore, doxazosin resulted in a considerable elevation in Smad4 and TIEG protein expression (6 h). A 'latent' increase in TGF-beta mRNA expression was detected after 48 h of treatment. These findings suggest that the quinazoline-based doxazosin mediates prostate cancer apoptosis by initially inducing the expression of TGF-beta1 signalling effectors and subsequently I kappa B alpha. The present study provides an initial insight into the molecular targets of the apoptotic action of quinazolines against prostate cancer cells.
Partin
J V
JV
Division of Urology, Department of Surgery, University of Kentucky Medical Center, Lexington, KY 40536, USA.
Anglin
I E
IE
Kyprianou
N
N
D000091162:AMP-Activated Protein Kinase Kinases; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000494:pharmacology; D017292:Doxazosin / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D011799:Quinazolines; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D017292:Doxazosin