Evidence indicates that a diet rich in omega (omega)-6 polyunsaturated fatty acids (PUFAs) [e.g., linoleic acid (LA)] increases prostate cancer (PCa) risk, whereas a diet rich in omega-3 decreases risk. Precisely how these PUFAs affect disease development remains unclear. So we examined the roles that PUFAs play in PCa, and we determined if increased omega-3 consumption can impede tumor growth. We previously demonstrated an increased expression of an omega-6 LA-metabolizing enzyme, 15-lipoxygenase-1 (15-LO-1, ALOX15), in prostate tumor tissue compared with normal adjacent prostate tissue, and that elevated 15-LO-1 activity in PCa cells has a protumorigenic effect. A PCa cell line, Los Angeles Prostate Cancer-4 (LAPC-4), expresses prostate-specific antigen (PSA) as well an active 15-LO-1 enzyme. Therefore, to study whether or not the protumorigenic role of 15-LO-1 and dietary omega-6 LA can be modulated by altering omega-3 levels through diet, we surgically removed tumors caused by LAPC-4 cells (mouse model to simulate radical prostatectomy). Mice were then randomly divided into three different diet groups-namely, high omega-6 LA, high omega-3 stearidonic acid (SDA), and no fat-and examined the effects of omega-6 and omega-3 fatty acids in diet on LAPC-4 tumor recurrence by monitoring for PSA. Mice in these diet groups were monitored for food consumption, body weight, and serum PSA indicative of the presence of LAPC-4 cells. Fatty acid methyl esters from erythrocyte membranes were examined for omega-6 and omega-3 levels to reflect long-term dietary intake. Our results provide evidence that prostate tumors can be modulated by the manipulation of omega-6:omega-3 ratios through diet and that the omega-3 fatty acid SDA [precursor of eicosapentaenoic acid (EPA)] promotes apoptosis and decreases proliferation in cancer cells, causing decreased PSA doubling time, compared to omega-6 LA fatty acid, likely by competing with the enzymes of LA and AA pathways, namely, 15-LO-1 and cyclooxygenases (COXs). Thus, EPA and DHA (major components of fish oil) could potentially be promising dietary intervention agents in PCa prevention aimed at 15-LO-1 and COX-2 as molecular targets. These observations also provide clues as to its mechanisms of action.

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The main objectives of our study were to determine the bioavailability of omega-3 (omega-3) to the tumor, to understand its mechanisms, and to determine the feasibility of targeting the omega-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 omega-6 linoleic acid (LA), high omega-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) omega-3 and omega-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 omega-6 diet-fed mice compared with the tumors from the omega-3 SDA-fed mice. Further, increased apoptosis was observed in tumors from omega-3 SDA diet-fed mice versus tumors from omega-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 omega-6/omega-3 ratios, and other major enzymes (elongase, Delta [Delta]-5-desaturase, and Delta-6-desaturase) of omega-6 catabolic pathways from the tumors. We observed a 2.7-fold increase in the omega-6/omega-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 Delta-6-desaturase and Delta-9 desaturase enzyme activities and reduced estimated Delta-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 omega-3 fatty acids in slowing prostate cancer growth by altering omega-6/omega-3 ratios through diet and by promoting apoptosis and inhibiting proliferation in tumors by directly competing with omega-6 fatty acids for 15-LO-1 and COX-2 activities.

Diets high in fat seem to correspond with an increased risk of certain forms of cancer, including bladder BlCa. This preliminary study examined the expression and enzyme activity profile of the polyunsaturated fatty acid metabolizing enzyme 15-Lipoxygenase-1 (15-LO-1) in human tissues from normal bladder and bladder tumors (stages CIS-T3/T4). Human tissue samples from normal (donor) bladder and bladder tumors (stages CIS-T3/T4; non-Bacillus Calmette-Guerin-treated) were grossly microdissected and analyzed for 15-LO-1 protein expression [immunohistochemistry (IHC)/Western blot], mRNA expression (quantitative real-time polymerase chain reaction) and enzyme activity profiles. Our results demonstrated that 15-LO-1 expression (protein/mRNA) and enzyme activity varied with BlCa progression. Specifically, IHC analyses of 15-LO-1 protein levels revealed decreased expression with increased bladder tumor stage. In particular, a statistically significant decrease in 15-LO-1 expression in stage T3/T4 bladder tumors compared with normal tissues (P<0.001) was observed. In agreement with IHC results, Western blot, quantitative real-time polymerase chain reaction, and enzymatic activity analyses demonstrated increased 15-LO-1 protein, mRNA, and enzyme activity, respectively, in normal human bladder tissues in comparison with stage T3/T4 human bladder tumors. Our finding of variable 15-LO-1 expression and enzyme activity in bladder tissues suggests a role for 15-LO-1 in bladder carcinogenesis.

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