The transcriptomics of de novo androgen biosynthesis in prostate cancer cells following androgen reduction.
The progression of prostate cancer to the castration-recurrent phenotype remains a major problem medically. The present study examined the transcriptomics of de novo androgen synthesis as a potential mechanism to escape from dependence on circulating androgen. VCaP, LNCaP and LAPC4 cells were acclimated to 1 nM testosterone for five generations before subjecting them to a reduced level of 0.03 nM testosterone. Changes in gene expression were quantified using qRT-PCR. Analyses of the cholesterol biosynthesis pathway and the Δ4, Δ5 and backdoor steroidogenic pathways were carried out. VCaP cells showed no change in the transcriptome of cholesterol biosynthesis. However, several receptors for cholesterol transport were upregulated. The Δ4 and Δ5 steroidogenic pathways, but not the backdoor pathway, were stimulated. Additionally, androgen receptor (AR) expression was increased. Taken together, the above changes might allow recovery of AR activity to a near normal level. In contrast, LNCaP cells showed only minimal adjustment in the transcriptome of steroidogenesis. LAPC4 cells were equally unresponsive to boosting the machinery of androgen production. In brief, our results suggest that the VCaP model is an appropriate model for further investigation of targeting the androgen-AR axis to block the emergence of castration-resistant prostate cancer.
Cheng
Jinrong
J
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
Wu
Yue
Y
Mohler
James L
JL
Ip
Clement
C
D000728:Androgens / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger; D011944:Receptors, Androgen / Q000187:drug effects / Q000235:genetics; D013739:Testosterone / Q000096:biosynthesis / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D000728:Androgens; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013739:Testosterone; D002784:Cholesterol
Endocrinology. 1996 Oct;137(10):4468-74
8828509
Prostate. 1998 Apr 1;35(1):63-70
9537601
J Natl Cancer Inst. 2008 Nov 5;100(21):1511-8
18957682
Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4077-80
9539689
Cancer Res. 2007 May 15;67(10):5033-41
17510436
Cancer Res. 2009 Mar 15;69(6):2305-13
19244107
Cancer Res. 2002 Feb 15;62(4):1008-13
11861374
J Clin Oncol. 2007 Apr 20;25(12):1596-605
17404365
Biochem Biophys Res Commun. 1998 Jul 30;248(3):511-4
9703956
Cancer Res. 2008 Jul 1;68(13):5469-77
18593950
Mol Endocrinol. 1993 Dec;7(12):1541-50
8145761
J Natl Cancer Inst. 2008 Feb 6;100(3):170-83
18230794
Curr Opin Clin Nutr Metab Care. 2006 Jul;9(4):379-85
16778565
Nat Rev Cancer. 2001 Oct;1(1):34-45
11900250
Clin Cancer Res. 2005 Jul 1;11(13):4653-7
16000557
Prostate. 2009 Feb 15;69(3):293-316
19023869
Cancer Res. 2006 Mar 1;66(5):2815-25
16510604
Endocr Rev. 2004 Dec;25(6):947-70
15583024
Proc Natl Acad Sci U S A. 1979 Jul;76(7):3330-7
226968
Endocrinology. 1999 Mar;140(3):1481-91
10067877
Nat Clin Pract Oncol. 2009 Jan;6(1):12-3
18957947
Cancer Res. 2008 Jun 1;68(11):4447-54
18519708
Proc Natl Acad Sci U S A. 1995 May 23;92(11):4778-82
7761400
J Clin Endocrinol Metab. 2006 Oct;91(10):3850-6
16882745
Cancer Epidemiol Biomarkers Prev. 2007 Nov;16(11):2226-32
18006910
Mol Cell Endocrinol. 2008 Nov 25;295(1-2):115-20
18782595
Cancer Res. 2008 Aug 1;68(15):6407-15
18676866
Clin Cancer Res. 2005 Jun 15;11(12):4365-71
15958619
Mol Endocrinol. 2001 Oct;15(10):1817-28
11579213
J Biol Chem. 2004 Jul 23;279(30):30938-44
15145948
Clin Cancer Res. 2004 Jan 15;10(2):440-8
14760063
Nat Med. 2004 Jan;10(1):33-9
14702632
Trends Endocrinol Metab. 2004 Nov;15(9):432-8
15519890
Biochem Biophys Res Commun. 1990 Dec 14;173(2):534-40
2260966
Steroids. 2004 Dec;69(13-14):795-801
15582534
Cancer Res. 1998 Dec 15;58(24):5718-24
9865729
Am J Pathol. 2004 Jan;164(1):217-27
14695335
J Clin Oncol. 2008 Oct 1;26(28):4563-71
18645193