title: Prazosin induces p53-mediated autophagic cell death in H9C2 cells.
abstract: Prazosin, a quinazoline-based α(1)-adrenoceptor antagonist, is known to induce cell death, and this effect is independent of its α-blockade activity. However, the detailed molecular mechanisms involved are still not fully understood. In this study, we found that prazosin, but not doxazosin, could induce patterns of autophagy in H9C2 cells, including intracellular vacuole formation, microtubule-associated protein 1 light chain 3 (LC3) conversion, and acidic vesicular organelle (AVO) augmentation. Western blot analysis of phosphorylated proteins showed that exposure to prazosin increased the levels of phospho-p53 and phospho-adenosine monophosphate-activated protein kinase (AMPK) but dramatically decreased the levels of phospho-mammalian target of rapamycin (mTOR), phospho-protein kinase B (Akt), and phospho-ribosomal protein S6 kinase (p70S6K). Furthermore, although pretreatments with the pharmacological autophagy inhibitor 3-methyladenine and the p53 inhibitor pifithrin-α suppressed prazosin-induced AVO formation, they did not reverse prazosin-induced decline in cell viability but enhanced prazosin-induced caspase-3 activation. From these results we suggest that prazosin induces autophagic cell death via a p53-mediated mechanism. When the autophagy pathway was inhibited, prazosin still induced programmed cell death, at least in part through apoptotic caspase-3 cascade enhancement. Thus, our results indicate a potential new target in prazosin-induced cell death.
authors: Institute of Pharmacology, College of Medicine, National Taiwan University, No. 1 Sec. 1 Jen-Ai Road, Taipei, Taiwan.
authors: Yi-Fan
authors: YF
authors: Yang
authors: Chau-Chung
authors: CC
authors: Wu
authors: Wen-Pin
authors: WP
authors: Chen
authors: Yuh-Lien
authors: YL
authors: Chen
authors: Ming-Jai
authors: MJ
authors: Su
references: Annu Rev Genet. 2009;43:67-93
references: 19653858
references: Naunyn Schmiedebergs Arch Pharmacol. 2009 Dec;380(6):473-7
references: 19904527
references: Growth Factors. 2007 Aug;25(4):209-26
references: 18092230
references: Acta Pharmacol Sin. 2010 Sep;31(9):1208-12
references: 20729871
references: Cancer Biol Ther. 2011 Jan 15;11(2):157-68
references: 21228626
references: Circ Res. 2009 Jan 30;104(2):150-8
references: 19179668
references: Circulation. 2003 Jan 7;107(1):127-31
references: 12515754
references: Cancer Res. 2004 Apr 1;64(7):2627-33
references: 15059920
references: Nat Cell Biol. 2007 Oct;9(10):1102-9
references: 17909521
references: Methods Cell Biol. 1994;41:185-94
references: 7532261
references: Naunyn Schmiedebergs Arch Pharmacol. 2009 Dec;380(6):561-7
references: 19727674
references: JAMA. 2000 Apr 19;283(15):1967-75
references: 10789664
references: Cardiovasc Res. 2006 Jul 1;71(1):118-28
references: 16631627
references: Autophagy. 2008 Feb;4(2):151-75
references: 18188003
references: Neoplasia. 2007 Oct;9(10):830-9
references: 17971903
references: Urol Res. 2004 Aug;32(4):261-5
references: 15221243
references: Cell Death Differ. 2009 Jan;16(1):31-8
references: 19008922
references: N Engl J Med. 1986 Jun 12;314(24):1547-52
references: 3520315
references: Autophagy. 2007 Nov-Dec;3(6):542-5
references: 17611390
references: Acta Physiol (Oxf). 2009 May;196(1):65-80
references: 19245654
references: Cancer Lett. 2009 Jun 18;278(2):130-138
references: 19004545
references: Nat Rev Cancer. 2009 Oct;9(10):691-700
references: 19759539
references: Autophagy. 2011 Jun;7(6):565-71
references: 21099252
references: Trends Cell Biol. 2010 Jun;20(6):363-9
references: 20303758
references: Bioorg Med Chem. 2010 Apr 1;18(7):2639-44
references: 20227281
references: Pharmacol Res. 2010 May;61(5):437-48
references: 20026273