Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity

X. Zuo; Y. Wu; J. S. Morris; J. B. Stimmel; L. M. Leesnitzer; S. M. Fischer; S. M. Lippman; I. Shureiqi

doi:10.1038/sj.onc.1209160

Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity

X. Zuo, Y. Wu, J. S. Morris, J. B. Stimmel, L. M. Leesnitzer, S. M. Fischer, S. M. Lippman, I. Shureiqi

Research output: Contribution to journal › Article › peer-review

95 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1225-1241
Number of pages	17
Journal	Oncogene
Volume	25
Issue number	8
DOIs	https://doi.org/10.1038/sj.onc.1209160
State	Published - Feb 23 2006

Keywords

15-Lipoxygenase-1
Colon cancer
PPAR-delta
PPAR-gamma

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

Access to Document

10.1038/sj.onc.1209160

Cite this

@article{2a13a0974e624859a189e59eb7cb7292,

title = "Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity",

abstract = "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.",

keywords = "15-Lipoxygenase-1, Colon cancer, PPAR-delta, PPAR-gamma",

author = "X. Zuo and Y. Wu and Morris, {J. S.} and Stimmel, {J. B.} and Leesnitzer, {L. M.} and Fischer, {S. M.} and Lippman, {S. M.} and I. Shureiqi",

note = "Funding Information: We thank Dr Reuben Lotan for his critical review of the manuscript and helpful comments. We also thank Karen Phillips from the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for editing the manuscript. In addition, we acknowledge the technical assistance of Dongning Chen. This work was supported in part by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services R01 Grant CA104278 (to IS); the American Cancer Society Scholar Award RSG-04-020-01-CNE (to IS); National Institute of Environmental Health Sciences, NIH Center Grant ES07784; and funding from The Jerry and Maury Rubenstein Foundation.",

year = "2006",

month = feb,

day = "23",

doi = "10.1038/sj.onc.1209160",

language = "English (US)",

volume = "25",

pages = "1225--1241",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Nature Publishing Group",

number = "8",

}

TY - JOUR

T1 - Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity

AU - Zuo, X.

AU - Wu, Y.

AU - Morris, J. S.

AU - Stimmel, J. B.

AU - Leesnitzer, L. M.

AU - Fischer, S. M.

AU - Lippman, S. M.

AU - Shureiqi, I.

N1 - Funding Information: We thank Dr Reuben Lotan for his critical review of the manuscript and helpful comments. We also thank Karen Phillips from the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for editing the manuscript. In addition, we acknowledge the technical assistance of Dongning Chen. This work was supported in part by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services R01 Grant CA104278 (to IS); the American Cancer Society Scholar Award RSG-04-020-01-CNE (to IS); National Institute of Environmental Health Sciences, NIH Center Grant ES07784; and funding from The Jerry and Maury Rubenstein Foundation.

PY - 2006/2/23

Y1 - 2006/2/23

N2 - 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.

AB - 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.

KW - 15-Lipoxygenase-1

KW - Colon cancer

KW - PPAR-delta

KW - PPAR-gamma

UR - http://www.scopus.com/inward/record.url?scp=33644509271&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33644509271&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1209160

DO - 10.1038/sj.onc.1209160

M3 - Article

C2 - 16288226

AN - SCOPUS:33644509271

SN - 0950-9232

VL - 25

SP - 1225

EP - 1241

JO - Oncogene

JF - Oncogene

IS - 8

ER -

Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this