Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity.
Peroxisome proliferator-activated receptors (PPARs) are transcription factors that strongly influence molecular events in normal and cancer cells. PPAR-beta/delta (PPAR-b/d) overexpression suppresses the activity of PPAR-gamma (PPAR-g) and PPAR-alpha. This interaction has been questioned, however, by studies with synthetic ligands of PPARs in PPAR-b/d-null cells, and it is not known whether an interaction between PPAR-b/d and PPAR-g exists, especially in relation to the signaling by natural PPAR ligands. Oxidative metabolites of linoleic and arachidonic acids are natural ligands of PPARs. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), the main product of 15-lipoxygenase-1 (15-LOX-1) metabolism of linoleic acid, downregulates PPAR-b/d. We tested (a) whether PPAR-b/d expression modulates PPAR-g activity in experimental models of the loss and gain of PPAR-b/d function in colon cancer cells and (b) whether 15-LOX-1 formation of 13-S-HODE influences the interaction between PPAR-b/d and PPAR-g. We found that (a) 15-LOX-1 formation of 13-S-HODE promoted PPAR-g activity, (b) PPAR-b/d expression suppressed PPAR-g activity in models of both loss and gain of PPAR-b/d function, (c) 15-LOX-1 activated PPAR-g by downregulating PPAR-b/d, and (d) 15-LOX-1 expression induced apoptosis in colon cancer cells via modulating PPAR-b/d suppression of PPAR-g. These findings elucidate a novel mechanism of the signaling by natural ligands of PPARs, which involves modulating the interaction between PPAR-b/d and PPAR-g.
Zuo
X
X
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77230-1439, USA.
Wu
Y
Y
Morris
J S
JS
Stimmel
J B
JB
Leesnitzer
L M
LM
Fischer
S M
SM
Lippman
S M
SM
Shureiqi
I
I
D000256:Adenoviridae / Q000235:genetics; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D019787:Linoleic Acid / Q000494:pharmacology*; D008041:Linoleic Acids / Q000378:metabolism; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048068:PPAR-beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
D008041:Linoleic Acids; D047494:PPAR delta; D047495:PPAR gamma; D048068:PPAR-beta; C024348:13-hydroxy-9,11-octadecadienoic acid; D019787:Linoleic Acid; D001093:Arachidonate 15-Lipoxygenase