Prostate Tumor Growth Can Be Modulated by Dietarily Targeting the 15-Lipoxygenase-1 and Cyclooxygenase-2 Enzymes

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2009-07, Vol.11 (7), p.692-699
• Main Authors: Kelavkar, Uddhav P., Hutzley, Justin, McHugh, Kevin, Allen, Kenneth G.D., Parwani, Anil
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Arachidonate 15-Lipoxygenase - metabolism; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Cyclooxygenase 2 - metabolism; Diet; Erythrocyte Membrane - chemistry; Erythrocyte Membrane - metabolism; Fatty Acids, Omega-3 - pharmacology; Humans; Immunohistochemistry; Male; Mice; Mice, Nude; Prostatic Neoplasms - diet therapy; Prostatic Neoplasms - enzymology
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.09334

The main objectives of our study were to determine the bioavailability of omega-3 (ω-3) to the tumor, to understand its mechanisms, and to determine the feasibility of targeting the ω-6 polyunsaturated fatty acids (PUFAs) metabolizing 15-lipoxygenase-1 (15-LO-1) and cyclooxygenase-2 (COX-2) pathways. Nude mice injected subcutaneously with LAPC-4 prostate cancer cells were randomly divided into three different isocaloric (and same percent [%] of total fat) diet groups: high ω-6 linoleic acid (LA), high ω-3 stearidonic acid (SDA) PUFAs, and normal (control) diets. Tumor growth and apoptosis were examined as end points after administration of short-term (5 weeks) ω-3 and ω-6 fatty acid diets. Tumor tissue membranes were examined for growth, lipids, enzyme activities, apoptosis, and proliferation. Tumors from the LA diet-fed mice exhibited the most rapid growth compared with tumors from the control and SDA diet-fed mice. Moreover, a diet switch from LA to SDA caused a dramatic decrease in the growth of tumors in 5 weeks, whereas tumors grew more aggressively when mice were switched from an SDA to an LA diet. Evaluating tumor proliferation (Ki-67) and apoptosis (caspase-3) in mice fed the LA and SDA diets suggested increased percentage proliferation index from the ω-6 diet-fed mice compared with the tumors from the ω-3 SDA-fed mice. Further, increased apoptosis was observed in tumors from ω-3 SDA diet-fed mice versus tumors from ω-6 diet-fed mice. Levels of membrane phospholipids of red blood cells reflected dietary changes and correlated with the levels observed in tumors. Linoleic or arachidonic acid and metabolites (eicosanoid/prostaglandins) were analyzed for 15-LO-1 and COX-2 activities by high-performance liquid chromatography. We also examined the percent unsaturated or saturated fatty acids in the total phospholipids, PUFA ω-6/ω-3 ratios, and other major enzymes (elongase, Delta [Δ]-5-desaturase, and Δ-6-desaturase) of ω-6 catabolic pathways from the tumors. We observed a 2.7-fold increase in the ω-6/ω-3 ratio in tumors from LA diet-fed mice and a 4.2-fold decrease in the ratio in tumors from the SDA diet-fed mice. There was an increased Δ-6-desaturase and Δ-9 desaturase enzyme activities and reduced estimated Δ-5-desaturase activity in tumors from mice fed the SDA diet. Opposite effects were observed in tumors from mice fed the LA diet. Together, these observations provide mechanistic roles of ω-3 fatty acids in slowing prostate cancer growth by alteri