The 15-lipoxygenase-1 product 13-
            <i>S</i>
            -hydroxyoctadecadienoic acid down-regulates PPAR-δ to induce apoptosis in colorectal cancer cells

Shureiqi, Imad; Jiang, Wei; Zuo, Xiangsheng; Wu, Yuanqing; Stimmel, Julie B.; Leesnitzer, Lisa M.; Morris, Jeffrey S.; Fan, Hui; Fischer, Susan M.; Lippman, Scott M.

doi:10.1073/pnas.1631086100

Cited by 213 publications

(204 citation statements)

References 20 publications

(28 reference statements)

Supporting

Mentioning

192

Contrasting

Unclassified

Order By: Relevance

“…Peroxisome proliferatoractivated receptord may mediate the antiapoptotic effect through activation by prostacyclin (PGI(2)), a major prostaglandin with antiapoptotic activity (Gupta et al, 2000;Cutler et al, 2003). There is also cumulative evidence regarding the antiapoptotic effects of PPARd in keratinocyte and colon cancer cells (Michalik et al, 2001;Di-Poi et al, 2002;Shureiqi et al, 2003;Gupta et al, 2004). These findings suggest that PPARd may play a certain tumour-promoting role in intestinal tumours or CRC cells by modulating cell survival and apoptosis, which is in line with our observation that PPARd was exclusively expressed in those CRC cells that also exhibited highly malignant morphology.…”

Section: Discussionsupporting

confidence: 88%

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

et al. 2006

View full text Add to dashboard Cite

Whether peroxisome proliferator-activated receptor (PPAR) d is a good target for the chemoprevention and/or treatment of colorectal cancer (CRC) remains controversial. Our goal was to examine PPARd expression in multistage carcinogenesis of the colorectum and to assess the relevance of PPARd in CRC. Immunohistochemical analysis indicated that PPARd expression increased from normal mucosa to adenomatous polyps to CRC. In cancer tissues, the PPARd protein was accumulated only in those cancer cells with highly malignant morphology, as represented by a large-sized nucleus, round-shaped nucleus, and presence of clear nucleoli. Interestingly, the cancer tissue often contained both PPARd-positive and -negative areas, each retaining their respective specific morphological features. Moreover, this pattern persisted even when PPARd-positive and -negative cells were aligned next to each other within a single cancer nest or gland and was present in the majority of CRC cases. Immunohistochemistry for Ki-67 proliferation marker showed no significant correlation between Ki-67 and PPARd in CRC samples. Based on Western blot analysis and quantitative RT -PCR, high PPARd protein expression correlated with high PPARd mRNA levels. Peroxisome proliferator-activated receptor d may have a supporting role in tumorigenesis, and the close association between PPARd expression and malignant morphology of CRC cells suggests a pivotal role in cancer tissue.

show abstract

Section: Discussionsupporting

confidence: 88%

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

et al. 2006

View full text Add to dashboard Cite

show abstract

“…1 and 2). Activation of PPARα and PPARγ by 13(S)-HODE has been observed previously [30], although this molecule has been reported to be an inhibitor of PPARβ/δ in colon epithelial cells [31]. Our data indicating 13(S)-HODE being a PPARβ/δ agonist in preadipocytes may suggest cell-type specific phenomena (Fig.…”

Section: Discussionsupporting

confidence: 71%

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

Coleman

Prabhu

Thompson

et al. 2007

Free Radical Biology and Medicine

103

View full text Add to dashboard Cite

Liver insufficiency and damage is a major cause of death and disease worldwide and may result from exposure to environmental toxicants, specific combinations or dosages of pharmaceuticals and microbial metabolites. The generation of reactive intermediates, in particular 4-hydroxynonenal (4-HNE), is a common event in liver damage caused by a variety of hepatotoxic drugs and solvents. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in the transcriptional regulation of lipid metabolism as well as other biological functions. Importantly, we have observed that the PPARβ/δ −/− mouse is more susceptible to chemically-induced hepatotoxicity than its wildtype counterpart, and our objective in this study was to elucidate the mechanism(s) by which PPARβ/δ confers protection to hepatocytes. We hypothesized that PPARβ/ δ plays a protective role by responding to toxic lipids and altering gene expression accordingly. In support, oxidized-VLDL and constituents including 13-S-hydroxyoctadeca-dienoic acid (13(S)-HODE) and 4-HNE are PPARβ/δ ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPARβ/δ subtype while 4-hyroxy-hexenal (4-HHE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPARβ/δ activity with a synthetic agonist decreased sensitivity of hepatocytes to 4-HNE and other toxic agents, whereas inhibition of this receptor had the opposite result. Gene expression microarray analysis identified several important PPARβ/δ-regulated detoxification enzymes involved in 4-HNE metabolism that are regulated at the transcript level. This research established 4-HNE as an endogenous modulator of PPARβ/δ activity and raises the possibility that agonists of this nuclear receptor may be utilized to prevent or treat liver disease associated with oxidative damage.

show abstract

“…Finally, a preliminary study of three mice targeting PPARd in Apc Min mice suggested that, although PPARd is not essential for polyp formation, its removal may tend to result in smaller polyps, although this finding was not proven to be significantly different (Barak et al, 2002). This data, taken together with the fact that PPARd expression is regulated by nonsteroidal anti-inflammatory drugs (He et al, 1999;Park et al, 2001;Shureiqi et al, 2003), suggests PPARd is a potential target for intervention in intestinal tumourigenesis. Consequently, we have investigated the role of PPARd in tumourigenesis in two murine model systems.…”

mentioning

confidence: 99%

PPARδ status and Apc-mediated tumourigenesis in the mouse intestine

et al. 2004

View full text Add to dashboard Cite

Based on recent reports that peroxisome proliferatoractivated receptor delta (PPARd) activation promotes tumourigenesis, we have investigated the role of this protein in Apc-mediated intestinal tumourigenesis. We demonstrate that the inactivation of Apc in the adult small intestine, while causing the expected nuclear accumulation of b-catenin, does not cause the expected increase in PPARd mRNA or protein but conversely, the levels of PPARd mRNA and protein are lowered. Furthermore, we find that Apc Min PPARd-null mice exhibit an increased predisposition to intestinal tumourigenesis. Our data suggest that PPARd is not directly regulated by bcatenin, and that inhibition of PPARd activity is unlikely to be an appropriate strategy for the chemoprevention or chemotherapy of intestinal malignancies.

show abstract

The 15-lipoxygenase-1 product 13- S -hydroxyoctadecadienoic acid down-regulates PPAR-δ to induce apoptosis in colorectal cancer cells

Cited by 213 publications

References 20 publications

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

PPARδ status and Apc-mediated tumourigenesis in the mouse intestine

Contact Info

Product

Resources

About