Neutral cholesterol ester hydrolase 1 (nCEH1) regulates extracellular LDL-cholesterol metabolism to influence prostate cancer progression

Raftopulos NL1, Washaya TC1, Egert A1,2,3, Aishah A1, Varney B1, Nagarajan SR1, Butler LM4,5, Grewal T2, and Hoy AJ1

  1. The University of Sydney, Charles Perkins Centre, Discipline of Physiology, School of Medical Sciences, Sydney, New South Wales, 2006, Australia.
  2. Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
  3. Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
  4. Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, South Australia, 5005, Australia.
  5. South Australian Health and Medical Research Institute, Adelaide, South Australia, 5001, Australia.

Prostate cancer (PCa) remains a leading cause of cancer-related death in Australian men. Advanced PCa is initially treated by depleting androgens thereby removing a critical promotor of tumour growth; however, the low androgen environment exerts selective pressure on remaining PCa cells and the disease evolves into a lethal, aggressive form termed castrate resistant PCa (CRPC). Hypercholesterolemia is a major side effect of androgen deprivation and is linked to more aggressive disease and the development of CRPC. Also, high-grade PCa and metastases exhibit aberrant accumulation of esterified cholesterol. Cholesterol is stored in cytosolic lipid droplets as cholesterol esters (CE) and inhibition of CE formation impairs PCa progression. However, it is now known whether the mobilisation of cholesterol from CE influences CRPC cell proliferation. As expected, C4-2B cell (androgen receptor positive, androgen independent) grew normally in a low androgen environment (charcoal-stripped serum) but had lower CE levels than cells cultured in full serum. CE levels are regulated by Neutral Cholesterol Ester Hydrolase 1 (nCEH1), which hydrolyses CE to free cholesterol and a fatty acid, and inhibition of nCEH1 slowed growth in charcoal-stripped serum, suggesting that cholesterol stored in CE supports cell growth in a low androgen environment. Depletion of lipid-rich lipoproteins (LPDS) from the media reduced C4-2B cell growth and intracellular CE levels, and this was exacerbated in charcoal-stripped LPDS. Supplementation of LPDS with cholesterol-rich LDL fully restored C4-2B cell growth; however, nCEH1 inhibition ameliorated the ability of LDL supplementation to restore C4-2B cell growth in LPDS containing media. These data indicate that LDL-cholesterol promotes C4-2B PCa cell growth via an nCEH1-catalysed metabolism. Future studies aim to further characterise the mechanisms by which CE metabolism influences CRPC cell behaviour. * NLR & TCW contributed equally.