Central role of PPARα in the mechanism of action of hepatocarcinogenic peroxisome proliferators

Corton, J C; Lapinskas, Paula J.; Gonzalez, Frank J.

doi:10.1016/s0027-5107(99)00232-8

Cited by 99 publications

(59 citation statements)

References 78 publications

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“…The initial indication that the PPARs play a role in the etiology of cancer was the isolation of PPAR␣ as the mediator of the tumorpromoting effect of peroxisome proliferators, compounds that cause hepatocarcinomas in rodents (Corton et al 2000). PPAR␣ is now known to be expressed in colon tumors and overexpressed in human breast and prostate cancer (Collett et al 2000;Roberts-Thomson and Snyderwine 2000).…”

Section: Discussionmentioning

confidence: 99%

PPARγ signaling exacerbates mammary gland tumor development

Sáez¹,

Rosenfeld²,

Livolsi³

et al. 2004

Genes Dev.

173

148

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Breast cancer cell lines that express the nuclear peroxisome proliferator-activated receptor ␥ (PPAR␥) can be prompted to undergo growth arrest and differentiation when treated with synthetic PPAR␥ ligands. To evaluate the therapeutic potential of increased PPAR␥ signaling in vivo, we generated transgenic mice that express a constitutively active form of PPAR␥ in mammary gland. These mice are indistinguishable from their wild-type littermates. However, when bred to a transgenic strain prone to mammary gland cancer, bigenic animals develop tumors with greatly accelerated kinetics. Surprisingly, in spite of their more malignant nature, bigenic tumors are more secretory and differentiated. The molecular basis of this tumor-promoting effect may be an increase in Wnt signaling, as ligand activation of PPAR␥ potentiates Wnt function in an in vivo model of this pathway. These results suggest that once an initiating event has taken place, increased PPAR␥ signaling serves as a tumor promoter in the mammary gland. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily, ligand-responsive transcription factors that participate in many important physiological processes . Mammals have three different PPARs (PPAR␣, PPAR␦, PPAR␥) that form functional heterodimers with the retinoid receptor RXR. These complexes are chief regulators of lipid storage and catabolism. Native and oxidized polyunsaturated fatty acids bind the PPARs and stimulate their transcriptional activity. The function of the PPARs is also modulated by arachidonic acid derivatives, such as prostaglandins and eicosanoids.PPAR␥ is the best-characterized member of the family. Its most prominent role is to regulate differentiation of cell types with active lipid metabolism, such as adipocytes and macrophage foam cells Walczak and Tontonoz 2002). The importance of this receptor in lipid homeostasis and energy balance is accentuated by the widespread use of thiazolidinediones (TZDs), synthetic PPAR␥ ligands, as antidiabetic drugs. The existence of FDA-approved PPAR␥ agonists and the ability of this receptor to induce cellular differentiation encouraged us to explore whether stimulation of PPAR␥ activity could curtail malignant cell growth, in analogy with what is observed with retinoic acid in acute promyelocytic leukemia.A survey of tumors revealed that PPAR␥ is generally overexpressed in liposarcoma, colon, breast, and prostate carcinoma (Tontonoz et al. 1997;DuBois et al. 1998). When treated with PPAR␥ and RXR ligands, cell lines derived from these neoplasms undergo morphological transformation and growth arrest in vitro (Tontonoz et al. 1997;Elstner et al. 1998;Kubota et al. 1998;Mueller et al. 1998;Sarraf et al. 1998). Additional cell culture studies have suggested that lung, pancreatic, and hematopoietic tumor cells also respond to thiazolidinedione treatment (Sporn et al. 2001). These observations prompted trials to evaluate PPAR␥ agonists as therapeutics in human liposarcoma, colon, breast, and prostate cancer...

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Section: Discussionmentioning

confidence: 99%

PPARγ signaling exacerbates mammary gland tumor development

Sáez¹,

Rosenfeld²,

Livolsi³

et al. 2004

Genes Dev.

173

148

View full text Add to dashboard Cite

show abstract

“…These events require the expression/overexpression and activation of molecules not generally requisite for normal cellular functions. The initial indication that the PPARs are involved in the aetiology of cancer was the isolation of PPARa as the mediator of the tumour-promoting effect of peroxisome proliferators, compounds that cause heptocellular carcinoma in rodents (Corton et al, 2000). PPARa has been shown to be expressed in colon tumours and overexpressed in breast and prostate tumours (Collett et al, 2000;Roberts-Thomson and Snyderwine, 2000).…”

Section: Discussionmentioning

confidence: 99%

Enhanced expression of peroxisome proliferator-activated receptor gamma in epithelial ovarian carcinoma

et al. 2004

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The peroxisome proliferator-activated receptors (PPARs) belong to a subclass of nuclear hormone receptor that executes important cellular transcriptional functions. Previous studies have demonstrated the expression of PPARg in several tumours including colon, breast, bladder, prostate, lung and stomach. This study demonstrates the relative expression of PPARg in normal ovaries and different pathological grades of ovarian tumours of serous, mucinous, endometrioid, clear cell and mixed subtypes. A total of 56 ovarian specimens including 10 normal, eight benign, 10 borderline, seven grade 1, nine grade 2 and 12 grade 3 were analysed using immunohistochemistry. Immunoreactive PPARg was not expressed in normal ovaries. Out of eight benign and 10 borderline tumours, only one tumour in each group showed weak cytoplasmic PPARg expression. In contrast, 26 out of 28 carcinomas studied were positive for PPARg expression with staining confined to cytoplasmic and nuclear regions. An altered staining pattern of PPARg was observed in high-grade ovarian tumours with PPARg being mostly localized in the nuclei with little cytoplasmic immunoreactivity. On the other hand, predominant cytoplasmic staining was observed in lower-grade tumours. Significantly increased PPARg immunoreactivity was observed in malignant ovarian tumours (grade 1, 2 and 3) compared to benign and borderline tumours (w 2 ¼ 48.80, Po0.001). Western blot analyses showed significant elevation in the expression of immunoreactive PPARg in grade 3 ovarian tumours compared with that of normal ovaries and benign ovarian tumours (Po0.01). These findings suggest an involvement of PPARg in the onset and development of ovarian carcinoma and provide an insight into the regulation of this molecule in the progression of the disease.

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“…Induction of these genes may be related both to increased proliferation and DNA damage repair. PPAR␣ ligandinduced elevation in H 2 O 2 levels leading to oxidative stress and DNA damage is thought to be one possible mechanism contributing to hepatocarcinogenesis in rodents (13,26,72). Therefore, the differential expression of some of the stress-related genes presented under this category may be related to oxidative stress responses.…”

Section: Rnas Ten Different Control Rnas (C1-c10)mentioning

confidence: 99%

Liver gene expression in rats in response to the peroxisome proliferator-activated receptor-α agonist ciprofibrate

Yadetie

Lægreid

Bakke

et al. 2003

Physiological Genomics

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Fibrate class hypolipidemic drugs such as ciprofibrate activate the peroxisome proliferator-activated receptor-α (PPARα), which is involved in processes including lipid metabolism and hepatocyte proliferation in rodents. We examined the effects of ciprofibrate (50 mg/kg body wt per day for 60 days) on liver gene expression in rats using cDNA microarrays. The 60-day dosing period was chosen to elucidate both the metabolic and proliferative actions of this substance, while avoiding confounding effects from the hepatic carcinogenesis seen during more long-term stimulation. Ciprofibrate changed the expression of many genes including previously known PPARα agonist-responsive genes involved in processes such as lipid metabolism and inflammatory responses. In addition, many novel candidate genes involved in sugar metabolism, transcription, signal transduction, cell proliferation, and stress responses appeared to be differentially regulated in ciprofibrate-dosed rats. Ciprofibrate also resulted in significant increases in liver weight and hepatocyte proliferation. The cDNA microarray results were confirmed by Northern blot analysis for selected genes. This study thus identifies many genes that appear to be differentially regulated in ciprofibrate-dosed rats, and some of these are potential targets of PPARα. The functional diversity of these candidate genes suggests that most of them are likely to be differentially regulated as indirect consequence of the many processes affected by ciprofibrate in rodent liver. Although caution is advisable in the interpretation of genome-wide expression data, the genes identified in the present study provide candidates for further studies that may give new insight into the mechanisms of action of peroxisome proliferators.

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Central role of PPARα in the mechanism of action of hepatocarcinogenic peroxisome proliferators

Cited by 99 publications

References 78 publications

PPARγ signaling exacerbates mammary gland tumor development

PPARγ signaling exacerbates mammary gland tumor development

Enhanced expression of peroxisome proliferator-activated receptor gamma in epithelial ovarian carcinoma

Liver gene expression in rats in response to the peroxisome proliferator-activated receptor-α agonist ciprofibrate

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