Apoptosis induction by 1alpha,25-dihydroxyvitamin D3 in prostate cancer.
Calcitriol [1alpha,25-dihydroxyvitamin D3] is the natural ligand of the vitamin D receptor (VDR). Using cultured prostate cancer (PC) cell lines, LN-CaP and ALVA-31, we studied the effects of 1alpha,25(OH)2-Vitamin D3 (VD3) on expression of several apoptosis-regulating proteins including: (a) Bcl-2 family proteins (Bcl-2, Bcl-X(L), Mcl-1, Bax, and Bak); (b) the heat shock protein 70-binding protein BAG1L; and (c) IAP family proteins (XIAP, cIAP1, and cIAP2). VD3 induced decreases in levels of antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1, BAG1L, XIAP, cIAP1, and cIAP2 (without altering proapoptotic Bax and Bak) in association with increases in apoptosis. In contrast to VDR-expressing LN-CaP and ALVA-31 cells, VDR-deficient prostate cancer line Du-145 demonstrated no changes in apoptosis protein expression after treatment with VD3. In sensitive PC cell lines, VD3 activates downstream effector protease, caspase-3, and upstream initiator protease caspase-9, the apical protease in the mitochondrial ("intrinsic") pathway for apoptosis, but not caspase-8, an initiator caspase linked to an alternative ("extrinsic") apoptosis pathway triggered by cytokine receptors. VD3 induced declines in antiapoptotic proteins and also stimulated cytochrome c release from mitochondria by a caspase-independent mechanism. Moreover, apoptosis induction by VD3 was suppressed by overexpressing Bcl-2, a known blocker of cytochrome c release, whereas the caspase-8 suppressor CrmA afforded little protection. Thus, VD3 is capable of inhibiting expression of multiple antiapoptotic proteins in VDR-expressing prostate cancer cells, leading to activation of the mitochondrial pathway for apoptosis.
Guzey
Meral
M
Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA.
Kitada
Shinichi
S
Reed
John C
JC
D017209:Apoptosis; D002117:Calcitriol / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008024:Ligands; D008297:Male; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013347:Subcellular Fractions; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D002120:Calcium Channel Agonists; D003574:Cytochrome c Group; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D020169:Caspases; D002117:Calcitriol