Activating Peroxisome Proliferator-Activated Receptor γ Mutant Promotes Tumor Growth <i>In vivo</i> by Enhancing Angiogenesis

Tian, Lifeng; Zhou, Jie; Casimiro, Mathew C.; Liu, Bing; Ojeifo, John; Wang, Min; Hyslop, Terry; Wang, Chenguang; Pestell, Richard G.

doi:10.1158/0008-5472.can-09-2067

Cited by 45 publications

(45 citation statements)

References 49 publications

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“…Similarly, rosiglitazone was shown to inhibit mouse lung tumor cell growth and metastasis in vivo through direct and indirect anti-angiogenic effects [82] . Although the above studies reveal important anticancer effects for PPARγ ligands, it is important to note that PPARγ signaling has also been associated with tumor promoter activity in some cancer cells such as colon and breast, and that this effect was linked to increased β-catenin, c-Myc, Angptl4 and Wnt 5 expression [83][84][85] (Table 1). PPARγ ligands enhanced 7,12-dimethylbenz(a)anthracene-induced rat mammary adenocarcinoma [86] and promoted colonic tumor growth in Apc Min mice fed a high-fat diet [87] .…”

Section: Pparγ and Angiogenesismentioning

confidence: 99%

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

Han

Roman²

2010

WJBC

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Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent nuclear transcription factors and members of the nuclear receptor superfamily. Of the three PPARs identified to date (PPARγ, PPARβ/δ, and PPARα), PPARγ has been studied the most, in part because of the availability of PPARγ agonists (also known as PPARγ ligands) and its significant effects on the management of several human diseases including type 2 diabetes, metabolic syndrome, cardiovascular disease and cancers. PPARγ is expressed in many tumors including lung cancer, and its function has been linked to the process of lung cancer development, progression and metastasis. Studies performed in gynogenic and xenograft models of lung cancer showed decreased tumor growth and metastasis in animals treated with PPARγ ligands. Furthermore, data are emerging from retrospective clinical studies that suggest a protective role for PPARγ ligands on the incidence of lung cancer. This review summarizes the research being conducted in this area and focuses on the mechanisms and potential therapeutic effects of PPARγ ligands as a novel anti-lung cancer treatment strategy.

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Section: Pparγ and Angiogenesismentioning

confidence: 99%

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

Han

Roman²

2010

WJBC

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“…ANGPTL4 has been implicated in regulation of angiogenesis [23,24,25,26,27,28]. Unlike angiopoietin 1, 2, and 4, ANGPTL4 exerts its effect independent of the TIE receptor family (TIE1 and TIE2) [54].…”

Section: Discussionmentioning

confidence: 99%

“…While ANGPTL4, a secreted glycoprotein encoded by the ANGPTL4 gene, is well known for its role in lipid metabolism [14,15,16,17,18,19,20,21,22], it is also thought to mediate angiogenesis with both anti- and pro-angiogenic effects [23,24,25,26,27,28,29]. ANGPTL4 has been reported to inhibit vascular permeability, tumor cell motility, invasiveness [30,31], sprouting [32], tubule-like structure formation [32,33,34,35], and vascular leakiness [31,34].…”

Section: Introductionmentioning

confidence: 99%

Angiopoietin-Like 4 <i>(ANGPTL4)</i> Gene Polymorphisms and Risk of Brain Arteriovenous Malformations

Mikhak¹,

Weinsheimer²,

Pawlikowska³

et al. 2011

Cerebrovasc Dis

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Background: Brain arteriovenous malformations (BAVM) are high-flow vascular lesions prone to intracranial hemorrhage (ICH). Abnormal angiogenesis is a key characteristic of BAVM tissue. Angiopoietin-like 4 (ANGPTL4), a secreted glycoprotein, is thought to be involved in angiogenesis and required for proper postnatal blood vessel partitioning. We investigated whether common single nucleotide polymorphisms (SNPs) in ANGPTL4 were associated with risk of BAVM or ICH. Methods and Results: We conducted a case-control study of 216 Caucasian BAVM cases and 246 healthy controls, and a secondary case-only analysis, comparing 83 ruptured (ICH) with 133 unruptured BAVM cases at presentation. Four tagSNPs in ANGPTL4 captured variation over a 10-kb region (rs2278236, rs1044250, rs11672433, and rs1808536) and were tested for association with BAVM or ICH. The minor allele (A) of rs11672433 (exon 6, Pro389Pro) was associated with an increased risk of BAVM (p = 0.006), which persisted after adjusting for multiple comparisons (p = 0.03). After adjustments for age and sex, carriers of the minor allele (A) remained at higher risk for BAVM compared to noncarriers (odds ratio, OR = 1.56; 95% confidence interval, CI = 1.01–2.41; p = 0.046) and risk of BAVM was increased with increasing copy of the minor A allele (OR = 1.49, 95% CI = 1.03–2.15; p_trend = 0.03). Five common haplotypes (frequency >1%) were inferred; overall haplotype distribution differed between BAVM cases and controls (χ² = 12.2, d.f. = 4, p = 0.02). Neither SNPs (p > 0.05) nor haplotype distribution (χ² = 1.1, d.f. = 4, p = 0.89) were associated with risk of ICH among BAVM cases. Conclusion: A synonymous SNP in ANGPTL4 and haplotypes carrying it are associated with risk of BAVM but not with ICH presentation in BAVM cases.

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“…Cerebral neuroprotection produced by PPARc agonists could be due to any of several mechanisms including oxidative stress modulation (Collino et al 2006), anti-inflammatory effects (Collino et al 2006;Sundararajan et al 2005), induction of mitochondrial biogenesis (Strum et al 2007) and/or through neuronal up-regulation of Bcl-2 (Fuenzalida et al 2007). In addition, several recent studies have shown that PPARc agonists reduce damage in cerebral ischemia by inhibition of matrix metalloproteinase-9 Wang et al 2009) or by enhancement of angiogenesis (Chu et al 2006), although the effects of PPARc agonists on angiogenesis in general are unclear and may vary between models and dosing regimes since both promotion (Biscetti et al 2008(Biscetti et al , 2009aTian et al 2009) and inhibition (Aljada et al 2008;Park et al 2009;Scoditti et al 2010) of angiogenesis have been reported following PPARc agonist administration.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the beneficial effects of PPARc agonists have been demonstrated in different animal models of CNS disorders such as multiple sclerosis (Diab et al 2004), global ischemia-induced hippocampal injury ) and focal ischemia-induced brain damage (Shimazu et al 2005;Luo et al 2006;Tureyen et al 2007;Chu et al 2006). The mechanism(s) underlying the beneficial effects of these agents is still unclear, but could be due to actions such as down-regulation of the inflammatory response (Sundararajan and Landreth 2004), upregulation of antioxidant enzymes (Shimazu et al 2005), regulation of cytokine production (Storer et al 2005;Xu et al 2008) or promotion of angiogenesis (Biscetti et al 2008(Biscetti et al , 2009aTian et al 2009). While the neuroprotective potential of PPARc agonists in ischemia is largely unexplored, the presence of PPARc receptors has been reported in the brain of CD1 mice (Cristiano et al 2005) and PPARc knockout mice have been shown to have increased susceptibility to ischemic brain damage (Zhao et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) Activation Confers Functional Neuroprotection in Global Ischemia

Fatehi‐Hassanabad

Tasker

2010

Neurotox Res

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The neuroprotective effect of rosiglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, has been investigated using both in vivo and in vitro models of global ischemia in CD1 mice. Behavioral tests were carried out prior to and at various times (up to 14 days) subsequent to bilateral common carotid artery occlusion followed by reperfusion. Mice at each time point were euthanized under anesthesia and the brain was removed, serially sliced and stained with 1% triphenyltetrazolium (TTC) to quantify infarct size. Administration of rosiglitazone (5 or 10 mg/kg, i.p.) 10 min prior to occlusion significantly reduced the postsurgical mortality rate (10-11 vs. 36%, P < 0.05). The higher dose of rosiglitazone (10 mg/kg) also significantly reduced the mean area of brain infarct at 1, 3, 7 and 14 days post-ischemia, reduced post-occlusion deficits in limb grasping and forelimb placing at various time points, and reduced total nitrite concentration in serum and brain homogenate at day 7 post-occlusion. To model global ischemia in vitro, coronal brain slices were incubated in oxygenated artificial cerebrospinal fluid (ACSF) in the presence of either glutamate (1 mM) or hydrogen peroxide (H(2)O(2)) (5 μM) for 30 min. Both H(2)O(2) and glutamate caused significant tissue damage, and co-incubation with rosiglitazone (5 μM) significantly reduced H(2)O(2)-induced damage but did not significantly reduce glutamate-induced brain damage in this model. Our observations provide further evidence for a neuroprotective effect of rosiglitazone in rodent models of ischemia.

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Activating Peroxisome Proliferator-Activated Receptor γ Mutant Promotes Tumor Growth In vivo by Enhancing Angiogenesis

Abstract: Peroxisome proliferator-activated receptor γ (PPARγ) is expressed in a variety of cancer cells. The addition of ligand activates the receptor by inducing a conformational change in the receptor, which can be recapitulated by mutation.

Cited by 45 publications

References 49 publications

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

Angiopoietin-Like 4 <i>(ANGPTL4)</i> Gene Polymorphisms and Risk of Brain Arteriovenous Malformations

Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) Activation Confers Functional Neuroprotection in Global Ischemia

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