A key regulator of cholesterol homoeostasis, SREBP-2, can be targeted in prostate cancer cells with natural products.
There is growing evidence showing that prostate cancer cells have perturbed cholesterol homoeostasis, accumulating cholesterol to promote cell growth. Consequently, cholesterol-lowering drugs such as statins are being evaluated in prostate cancer treatment. Furthermore, natural products such as betulin (from birch tree bark) and tocotrienol (a minor form of vitamin E) have been shown to lower cholesterol levels. Using these drugs and oxysterols, we have determined which aspects of cholesterol homoeostasis should be targeted in prostate cancer, e.g. cellular cholesterol levels are increased by the transcription factor SREBP-2 (sterol-regulatory-element-binding protein isoform 2), whereas LXR (liver X receptor) promotes cholesterol efflux. Whereas betulin exerted non-specific effects on cell viability, tocotrienols produced a strong direct correlation between SREBP-2 activity and cell viability. Mechanistically, tocotrienols lowered SREBP-2 activity by degrading mature SREBP-2 independently of the proteasome. In contrast, no correlation was seen between LXR activity and cell viability, implying that SREBP-2 is a better target than LXR for prostate cancer treatment. Lastly, androgen-dependent and -independent LNCaP cells were both sensitive to tocotrienols. Overall, this suggests that tocotrienols and other drugs targeting the SREBP-2 pathway are a potential therapeutic option for prostate cancer.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
James R
JR
Krycer
Lisa
L
Phan
Andrew J
AJ
Brown
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D002839:Chromans / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D024508:Tocotrienols / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology; D014810:Vitamin E / Q000031:analogs & derivatives / Q000494:pharmacology; D000094062:Betulinic Acid
D000972:Antineoplastic Agents, Phytogenic; D002784:Cholesterol; D002839:Chromans; D047908:Intracellular Signaling Peptides and Proteins; D000071518:Liver X Receptors; D008565:Membrane Proteins; D050505:Mutant Proteins; D009363:Neoplasm Proteins; D057093:Orphan Nuclear Receptors; D011994:Recombinant Proteins; D051782:Sterol Regulatory Element Binding Protein 2; D024508:Tocotrienols; D014315:Triterpenes; D014810:Vitamin E; C497390:SREBF2 protein, human; C102196:SREBP cleavage-activating protein; C082097:tocotrienol, delta; C013649:plastochromanol 8; C002503:betulin; D000094062:Betulinic Acid; C082032:tocotrienol, alpha