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), 3β-hydroxysteroid dehydrogenase (3β-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 ~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.

Blood lipid levels and prostate cancer risk; a cohort study

“…39 It has recently been shown that prostate cancer cells in advanced stages can synthesize androgens directly from cholesterol. 40 These findings might explain the suggested association between serum cholesterol levels and risk of aggressive forms of prostate cancer. Future studies are needed to confirm the exact role of cholesterol and other blood lipids in the development and progression of prostate cancer.…”

No Association between Egg Intake and Prostate Cancer Risk: A Meta-analysis

“…Eggs are an important source of cholesterol and choline, both of which are highly concentrated in prostate cancer cells. Cholesterol homeostasis is disrupted in malignant cells, leading to accumulation of cholesterol, which is a precursor of androgen and may alter signaling pathways to promote cancer progression (Freeman et al, 2004;Dillard et al, 2008). Choline is essential for a variety of cell functions involved in cancer growth and progression.…”

Paradigm Shift in the Concept of Hormonal Milieu of Prostate Cancer

“…[66] Androgen-independent prostate cancer cell lines synthesize testosterone from radio-labeled cholesterol in vitro, and human prostate cancer xenografts are capable of synthesizing DHT from acetate and cholesterol, confirming that tumoral androgen synthesis is possible. [67] Thus, experimental and clinical evidence suggests that the enzymes of steroid metabolism are activated in the prostate cancer with CRPC state, and might provide multiple new targets for therapeutic intervention. Moreover, substantial evidences suggest that CRPC may not, in fact, be androgen independent, but occurs in a setting of continued ARmediated signaling that is driven by the presence of residual tissue androgens.…”