PPAR<i>γ</i>, PTEN, and the Fight against Cancer

Teresi, Rosemary E.; Waite, Kristin

doi:10.1155/2008/932632

Cited by 30 publications

(22 citation statements)

References 35 publications

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“…Previous investigations have indicated that pancreatic cancer growth can be modulated by PTEN regulating agents such as TGF-beta (38) and PPAR-gamma PTEN (39). Our results show that BITC did not alter the protein or phosphorylated levels of PTEN in either BxPC-3 or PanC-1 cells (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Pancreatic Tumor Suppression by Benzyl Isothiocyanate Is Associated with Inhibition of PI3K/AKT/FOXO Pathway

Boreddy

Pramanik

Srivastava

2011

Clinical Cancer Research

159

138

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Purpose: Our previous studies have shown that benzyl isothiocyanate (BITC) suppress pancreatic cancer growth by inducing apoptosis but the molecular mechanism was unclear. In this study we hypothesized the involvement of PI3K/AKT/FOXO pathway in BITC-induced apoptosis.Experimental Design: Mice were implanted BxPC-3 tumor xenografts and orally gavaged with 12 mmol BITC. Plasma and tumor BITC concentration was estimated by liquid chromatography/tandem mass spectrometry. BxPC-3 and PanC-1 cells were used to elucidate PI3K/AKT/FOXO pathway. Electrophoretic mobility shift assay (EMSA), DNA binding activity, immunofluorescence, and gene transfection were used to delineate the mechanism.Results: BITC-treated mice showed 43% less tumor growth as compared with control mice and correlated well with the therapeutic concentrations of 6.5 mmol/L BITC achieved in plasma and 7.5 mmol/g BITC in tumor tissue. Western blot analyses and immunohistochemistry revealed that tumors from BITC-treated mice showed reduced phosphorylation of PI3K, AKT, PDK1, mTOR, FOXO1, and FOXO3a and increased apoptosis. Complementing our in vivo results, we made similar observations in a dose-and time-dependent manner in BITC-treated BxPC-3 and Panc-1 cells. Binding of FOXO1 with 14-3-3 proteins was also reduced drastically by BITC treatment indicating nuclear retention of FOXO1 and this observation was further confirmed with EMSA, immunofluorescence, DNA binding, and upregulation of FOXOresponsive proteins Bim, p27, and p21 in BxPC-3 cells. Overexpression of AKT by transient transfection significantly blocked the modulation of FOXO proteins and protected the cells from BITC-mediated apoptosis and growth suppression.Conclusions: Our results provide convincing evidence on the involvement of PI3K/AKT/FOXO pathway in BITC-mediated pancreatic tumor growth suppression.

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Section: Discussionmentioning

confidence: 99%

Pancreatic Tumor Suppression by Benzyl Isothiocyanate Is Associated with Inhibition of PI3K/AKT/FOXO Pathway

Boreddy

Pramanik

Srivastava

2011

Clinical Cancer Research

159

138

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“…The data are therefore consistent with the notion that SSc fibroblasts possess a gene expression signature reminiscent of TGFb signaling , but are activated in a fashion that is autonomous of canonical TGFb signaling but dependent on non-canonical TGFb signaling pathways (Trojanowska, 2009;Leask, 2011). One possible mechanism underlying the reduced PTEN expression in SSc fibroblasts could be due to reduced expression of peroxisome proliferator-activated receptor-g; peroxisome proliferator-activated receptor-g is reduced in SSc fibroblasts; and peroxisome proliferator-activated receptor-g can regulate PTEN expression (Teresi and Waite, 2008;Wei et al, 2010). Our data collectively suggest that PTEN normally suppresses fibrogenesis in vivo and that loss of PTEN expression is sufficient for fibrogenesis in vivo.…”

Section: Loss Of Pten Results In Fibrosismentioning

confidence: 99%

Loss of PTEN Expression by Dermal Fibroblasts Causes Skin Fibrosis

Parapuram

Elliott

et al. 2011

Journal of Investigative Dermatology

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Fibrosis represents a common pathway leading to organ failure and death in many diseases and has no effective therapy. Dysregulated repair and excessive tissue scarring provides a unifying mechanism for pathological fibrosis. The protein phosphatase and tensin homolog (PTEN) acts to dephosphorylate proteins, which promotes tissue repair and thus could be a key fibrogenic mediator. To test this hypothesis, we first showed that PTEN expression was reduced in skin fibroblasts from patients with the fibrotic autoimmune disease diffuse systemic sclerosis (dSSc). To evaluate whether this deficiency could be sufficient for fibrogenesis in vivo, we deleted PTEN in adult mouse fibroblasts. Compared with littermate control mice, loss of PTEN resulted in a 3-fold increase in dermal thickness due to excess deposition of collagen. PTEN-deleted fibroblasts showed elevated Akt phosphorylation and increased expression of connective tissue growth factor (CTGF/CCN2). Selective inhibition of the phosphatidylinositol 3-kinase/Akt pathway reduced the overexpression of collagen and CCN2 by PTEN-deficient fibroblasts. Overexpression of PTEN reduced the overexpression of type I collagen and CCN2 by dSSc fibroblasts. Thus, PTEN appears to be a potential in vivo master regulator of fibrogenesis; PTEN agonists may represent anti-fibrotic treatments.

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“…PPARγ has been suggested as a tumor suppressor in human follicular thyroid cancer (Shen and Chung, 2005; Teresi and Waite, 2008). PPARγ was shown to suppress proliferation and increase apoptosis of thyroid tumor cells by activating nuclear factor-κB signaling (Kato et al ., 2006).…”

Section: Resultsmentioning

confidence: 99%

Thyroid hormone receptors are tumor suppressors in a mouse model of metastatic follicular thyroid carcinoma

Zhao

et al. 2010

Oncogene

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Aberrant expression and mutations of thyroid hormone receptor genes (TRs) are closely associated with several types of human cancers. To test the hypothesis that TRs could function as tumor suppressors, we took advantage of mice with deletion of all functional TRs (TRα1−/− TRβ−/−mice). As these mice aged, they spontaneously developed follicular thyroid carcinoma with pathological progression from hyperplasia to capsular invasion, vascular invasion, anaplasia and metastasis to the lung, similar to human thyroid cancer. Detailed molecular analysis revealed that known tumor promoters such as pituitary tumor-transforming gene were activated and tumor suppressors such as peroxisome proliferator-activated receptor γ and p53 were suppressed during carcinogenesis. In addition, consistent with the human cancer, AKT–mTOR–p70S6K signaling and vascular growth factor and its receptor were activated to facilitate tumor progression. This report presents in vivo evidence that functional loss of both TRα1 and TRβ genes promotes tumor development and metastasis. Thus, TRs could function as tumor suppressors in a mouse model of metastatic follicular thyroid cancer.

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PPARγ, PTEN, and the Fight against Cancer

Cited by 30 publications

References 35 publications

Pancreatic Tumor Suppression by Benzyl Isothiocyanate Is Associated with Inhibition of PI3K/AKT/FOXO Pathway

Pancreatic Tumor Suppression by Benzyl Isothiocyanate Is Associated with Inhibition of PI3K/AKT/FOXO Pathway

Loss of PTEN Expression by Dermal Fibroblasts Causes Skin Fibrosis

Thyroid hormone receptors are tumor suppressors in a mouse model of metastatic follicular thyroid carcinoma

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