Androgen-independent Prostate Cancer Cells Acquire the Complete Steroidogenic Potential of Synthesizing Testosterone from Cholesterol

Overview

Journal Mol Cell Endocrinol

Specialties Cell Biology
Endocrinology
Molecular Biology

Date 2008 Sep 11

PMID 18782595

Citations 106

Authors

Paulette R Dillard

Ming-Fong Lin

Shafiq A Khan

Affiliations

Soon will be listed here.

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.

Citing Articles

Lipid Profile, PCSK9, ANGPTL3 and Lipoprotein (a) Levels in Men Diagnosed With Localized High-Grade Prostate Cancer and Men At-Risk of Prostate Cancer.

Bergeron A, Wong-Chong E, Joncas F, Castonguay C, Calon F, Seidah N Cancer Med. 2025; 14(3):e70587.

PMID: 39888285 PMC: 11783234. DOI: 10.1002/cam4.70587.

Metabolic adaptations in prostate cancer.

Pujana-Vaquerizo M, Bozal-Basterra L, Carracedo A Br J Cancer. 2024; 131(8):1250-1262.

PMID: 38969865 PMC: 11473656. DOI: 10.1038/s41416-024-02762-z.

Semaphorin 3C promotes de novo steroidogenesis in prostate cancer cells.

Yenki P, Bhasin S, Liu L, Nabavi N, Cheng C, Tam K Endocr Relat Cancer. 2023; 30(12).

PMID: 37800655 PMC: 10692650. DOI: 10.1530/ERC-23-0010.

Dissecting the effects of androgen deprivation therapy on cadherin switching in advanced prostate cancer: A molecular perspective.

Varisli L, Tolan V, Cen J, Vlahopoulos S, Cen O Oncol Res. 2023; 30(3):137-155.

PMID: 37305018 PMC: 10208071. DOI: 10.32604/or.2022.026074.

Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer.

Nguyen T, Sridaran D, Chouhan S, Weimholt C, Wilson A, Luo J Nat Commun. 2023; 14(1):3357.

PMID: 37296155 PMC: 10256812. DOI: 10.1038/s41467-023-38887-7.

References

Chen S, Karan D, Johansson S, Lin F, Zeckser J, Singh A . Prostate-derived factor as a paracrine and autocrine factor for the proliferation of androgen receptor-positive human prostate cancer cells. Prostate. 2007; 67(5):557-71. DOI: 10.1002/pros.20551. View

Denmeade S, Sokoll L, Dalrymple S, Rosen D, Gady A, Bruzek D . Dissociation between androgen responsiveness for malignant growth vs. expression of prostate specific differentiation markers PSA, hK2, and PSMA in human prostate cancer models. Prostate. 2003; 54(4):249-57. DOI: 10.1002/pros.10199. View

Cai C, Chen S, Zheng Z, Omwancha J, Lin M, Balk S . Androgen regulation of soluble guanylyl cyclasealpha1 mediates prostate cancer cell proliferation. Oncogene. 2006; 26(11):1606-15. DOI: 10.1038/sj.onc.1209956. View

Griffiths K, Morton M, Nicholson R . Androgens, androgen receptors, antiandrogens and the treatment of prostate cancer. Eur Urol. 1997; 32 Suppl 3:24-40. View

Chen C, Welsbie D, Tran C, Baek S, Chen R, Vessella R . Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004; 10(1):33-9. DOI: 10.1038/nm972. View

Nakamura Y, Suzuki T, Nakabayashi M, Endoh M, Sakamoto K, Mikami Y . In situ androgen producing enzymes in human prostate cancer. Endocr Relat Cancer. 2005; 12(1):101-7. DOI: 10.1677/erc.1.00914. View

Ismail A, Niswender G, MIDGLEY Jr A . Radioimmunoassay of testosterone without chromatography. J Clin Endocrinol Metab. 1972; 34(1):177-84. DOI: 10.1210/jcem-34-1-177. View

Cao X, Qin J, Xie Y, Khan O, Dowd F, Scofield M . Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells. Oncogene. 2006; 25(26):3719-34. DOI: 10.1038/sj.onc.1209408. View

Jemal A, Ward E, Hao Y, Thun M . Trends in the leading causes of death in the United States, 1970-2002. JAMA. 2005; 294(10):1255-9. DOI: 10.1001/jama.294.10.1255. View

10.

Titus M, Schell M, Lih F, Tomer K, Mohler J . Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005; 11(13):4653-7. DOI: 10.1158/1078-0432.CCR-05-0525. View

11.

Stanbrough M, Bubley G, Ross K, Golub T, Rubin M, Penning T . Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006; 66(5):2815-25. DOI: 10.1158/0008-5472.CAN-05-4000. View

12.

Gelmann E . Molecular biology of the androgen receptor. J Clin Oncol. 2002; 20(13):3001-15. DOI: 10.1200/JCO.2002.10.018. View

13.

Watari H, Arakane F, Moog-Lutz C, Kallen C, Tomasetto C, Gerton G . MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis. Proc Natl Acad Sci U S A. 1997; 94(16):8462-7. PMC: 22957. DOI: 10.1073/pnas.94.16.8462. View

14.

Unni E, Sun S, Nan B, McPhaul M, Cheskis B, Mancini M . Changes in androgen receptor nongenotropic signaling correlate with transition of LNCaP cells to androgen independence. Cancer Res. 2004; 64(19):7156-68. DOI: 10.1158/0008-5472.CAN-04-1121. View

15.

Hara T, Nakamura K, Araki H, Kusaka M, Yamaoka M . Enhanced androgen receptor signaling correlates with the androgen-refractory growth in a newly established MDA PCa 2b-hr human prostate cancer cell subline. Cancer Res. 2003; 63(17):5622-8. View

16.

El-Alfy M, Luu-The V, Huang X, Berger L, Labrie F, Pelletier G . Localization of type 5 17beta-hydroxysteroid dehydrogenase, 3beta-hydroxysteroid dehydrogenase, and androgen receptor in the human prostate by in situ hybridization and immunocytochemistry. Endocrinology. 1999; 140(3):1481-91. DOI: 10.1210/endo.140.3.6585. View

17.

Mostaghel E, Page S, Lin D, Fazli L, Coleman I, True L . Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007; 67(10):5033-41. DOI: 10.1158/0008-5472.CAN-06-3332. View

18.

Millena A, Reddy S, Bowling G, Khan S . Autocrine regulation of steroidogenic function of Leydig cells by transforming growth factor-alpha. Mol Cell Endocrinol. 2004; 224(1-2):29-39. DOI: 10.1016/j.mce.2004.07.004. View

19.

Castagnetta L, Carruba G, Traina A, Granata O, Markus M, Pavone-Macaluso M . Expression of different 17beta-hydroxysteroid dehydrogenase types and their activities in human prostate cancer cells. Endocrinology. 1997; 138(11):4876-82. DOI: 10.1210/endo.138.11.5497. View

20.

Ellem S, Risbridger G . Aromatase and prostate cancer. Minerva Endocrinol. 2006; 31(1):1-12. View