Organoids model distinct Vitamin E effects at different stages of prostate cancer evolution

• Published in: Scientific reports Vol. 7; no. 1; pp. 16285 - 14
• Main Authors: Njoroge, Rose N., Unno, Kenji, Zhao, Jonathan C., Naseem, Anum F., Anker, Jonathan F., McGee, Warren A., Nonn, Larisa, Abdulkadir, Sarki A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.11.2017; Nature Publishing Group
• Subjects: 13/1; 631/67/2195; 631/67/589/466; 631/67/70; 692/4025/1752; Antioxidants - metabolism; Benign; Cell death; Cell proliferation; Cell Proliferation - drug effects; Cell survival; Cells, Cultured; Computational Biology; Gene expression; Glucose transporter; Glycolysis; High-Throughput Nucleotide Sequencing; Humanities and Social Sciences; Humans; Male; Microarray Analysis; multidisciplinary; Organoids; Organoids - cytology; Organoids - drug effects; Oxidation; Oxygen Consumption - drug effects; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Selenium; Tissue Culture Techniques; Tumorigenesis; Vitamin E; Vitamin E - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-16459-2

Vitamin E increased prostate cancer risk in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) through unknown mechanisms while Selenium showed no efficacy. We determined the effects of the SELECT supplements on benign (primary), premalignant ( RWPE-1) and malignant (LNCaP) prostate epithelial organoids. While the supplements decreased proliferation and induced cell death in cancer organoids, they had no effect on the benign organoids. In contrast, Vitamin E enhanced cell proliferation and survival in the premalignant organoids in a manner that recapitulated the SELECT results. Indeed, while Vitamin E induced a pro-proliferative gene expression signature, Selenium alone or combined with Vitamin E produced an anti-proliferative signature. The premalignant organoids also displayed significant downregulation of glucose transporter and glycolytic gene expression pointing to metabolic alterations. Detached RWPE-1 cells had low ATP levels due to diminished glucose uptake and glycolysis which was rescued by Vitamin E through the activation of fatty acid oxidation (FAO). FAO inhibition abrogated the ATP rescue, diminished survival of the inner matrix detached cells, restoring the normal hollow lumen morphology in Vitamin E treated organoids. Organoid models therefore clarify the paradoxical findings from SELECT and demonstrate that Vitamin E promotes tumorigenesis in the early stages of prostate cancer evolution.