title: Androgen-independent prostate cancer cells acquire the complete steroidogenic potential of synthesizing testosterone from cholesterol.
abstract: The proliferation and differentiation of normal prostate epithelial cells depends upon the action of androgens produced by the testis. Prostate cancers retain the ability to respond to androgens in the initial stages of cancer development, but progressively become independent of exogenous androgens in advanced stages of the disease while maintaining the expression of functional androgen receptor (AR). In the present study, we have determined the potential of prostate cancer cells to synthesize androgens from cholesterol which may be involved in intracrine regulation of AR in advanced stages of the disease. Established androgen-independent prostate cancer cell lines, PC3 and DU145 cells, expressed mRNA and proteins for scavenger receptor type B1 (SRB1), steroidogenic acute regulatory (StAR) protein, cytochrome P450 cholesterol side chain cleavage (P450scc), 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and other enzymes involved in androgen biosynthesis. Expression of all these proteins and enzymes was significantly higher in the androgen-independent derivative of LNCaP prostate cancer cells (C81) than in the androgen-dependent cell line (C33). In serum-free cultures, the androgen-independent C81 cells secreted approximately 5-fold higher testosterone than C33 cells as determined in the conditioned media by immunoassays. These cells could also directly convert radioactive cholesterol into testosterone which was identified by thin layer chromatography. These results for the first time show that prostate cancer cells in advanced stages of the disease could synthesize androgens from cholesterol and hence are not dependent upon testicular and/or adrenal androgens.
authors.affiliation: Department of Biological Sciences, Clark Atlanta University, Atlanta, GA 30314, United States.
authors.forename: Paulette R
authors.initials: PR
authors.lastname: Dillard
authors.forename: Ming-Fong
authors.initials: MF
authors.lastname: Lin
authors.forename: Shafiq A
authors.initials: SA
authors.lastname: Khan
mesh_terms: D000728:Androgens / Q000378:metabolism*; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000728:Androgens; D012333:RNA, Messenger; D013739:Testosterone; D002784:Cholesterol
references.citation: Prostate. 2007 Apr 1;67(5):557-71
references.pmid: 17221842
references.citation: Prostate. 2003 Mar 1;54(4):249-57
references.pmid: 12539223
references.citation: Oncogene. 2007 Mar 8;26(11):1606-15
references.pmid: 16964290
references.citation: Eur Urol. 1997;32 Suppl 3:24-40
references.pmid: 9267783
references.citation: Nat Med. 2004 Jan;10(1):33-9
references.pmid: 14702632
references.citation: Endocr Relat Cancer. 2005 Mar;12(1):101-7
references.pmid: 15788642
references.citation: J Clin Endocrinol Metab. 1972 Jan;34(1):177-84
references.pmid: 5061771
references.citation: Oncogene. 2006 Jun 22;25(26):3719-34
references.pmid: 16449965
references.citation: JAMA. 2005 Sep 14;294(10):1255-9
references.pmid: 16160134
references.citation: Clin Cancer Res. 2005 Jul 1;11(13):4653-7
references.pmid: 16000557
references.citation: Cancer Res. 2006 Mar 1;66(5):2815-25
references.pmid: 16510604
references.citation: J Clin Oncol. 2002 Jul 1;20(13):3001-15
references.pmid: 12089231
references.citation: Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8462-7
references.pmid: 9237999
references.citation: Cancer Res. 2004 Oct 1;64(19):7156-68
references.pmid: 15466214
references.citation: Cancer Res. 2003 Sep 1;63(17):5622-8
references.pmid: 14500404
references.citation: Endocrinology. 1999 Mar;140(3):1481-91
references.pmid: 10067877
references.citation: Cancer Res. 2007 May 15;67(10):5033-41
references.pmid: 17510436
references.citation: Mol Cell Endocrinol. 2004 Sep 30;224(1-2):29-39
references.pmid: 15353178
references.citation: Endocrinology. 1997 Nov;138(11):4876-82
references.pmid: 9348218
references.citation: Minerva Endocrinol. 2006 Mar;31(1):1-12
references.pmid: 16498360
references.citation: Clin Cancer Res. 2004 Jan 15;10(2):440-8
references.pmid: 14760063
references.citation: Steroids. 1997 Jan;62(1):148-58
references.pmid: 9029730
references.citation: Arthritis Res Ther. 2005;7(5):R938-48
references.pmid: 16207335
references.citation: Am J Pathol. 2004 Jan;164(1):217-27
references.pmid: 14695335
references.citation: J Clin Endocrinol Metab. 2004 May;89(5):2434-41
references.pmid: 15126575
references.citation: Annu Rev Physiol. 2001;63:193-213
references.pmid: 11181954
references.citation: Prostate. 2002 Mar 1;50(4):222-35
references.pmid: 11870800
references.citation: Surg Gynecol Obstet. 1969 Jan;128(1):117
references.pmid: 5774991
references.citation: Nat Rev Cancer. 2001 Oct;1(1):34-45
references.pmid: 11900250