Elsevier

Neoplasia

Volume 8, Issue 2, February 2006, Pages 112-124
Neoplasia

Prostate Tumor Growth and Recurrence Can Be Modulated by the ω-6:ω-3 Ratio in Diet: Athymic Mouse Xenograft Model Simulating Radical Prostatectomy1

https://doi.org/10.1593/neo.05637Get rights and content
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open access

Abstract

Evidence indicates that a diet rich in omega (ω)-6 polyunsaturated fatty acids (PUFAs) [e.g., linoleic acid (LA)] increases prostate cancer (PCa) risk, whereas a diet rich in ω-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 ω-3 consumption can impede tumor growth. We previously demonstrated an increased expression of an ω-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 ω-6 LA can be modulated by altering ω-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 ω-6 LA, high ω-3 stearidonic acid (SDA), and no fat—and examined the effects of ω-6 and ω-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 ω-6 and ω-3 levels to reflect long-term dietary intake. Our results provide evidence that prostate tumors can be modulated by the manipulation of ω-6:ω-3 ratios through diet and that the ω-3 fatty acid SDA [precursor of eicosapentaenoic acid (EPA)] promotes apoptosis and decreases proliferation in cancer cells, causing decreased PSA doubling time, compared to ω-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.

Keywords

Polyunsaturated fatty acids
cancer prevention
radical prostatectomy
15-lipoxygenase-1
prostate cancer

Abbreviations

15-LO-1
15-lipoxygenase-1
AA
arachidonic acid
COX
cyclooxygenase
HETE
hydroxyeicosatetraenoic acid
HODE
hydroxyoctadecadienoic acid
LO
lipoxygenase
LA
linoleic acid
MSRP
mouse model to simulate radical prostatectomy
LAPC-4
Los Angeles Prostate Cancer-4
PUFA
polyunsaturated fatty acid
PSA
prostate-specific antigen

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1

This work was supported, in part, by American Cancer Society grant RSG-03-022-01 to U.P.K.