Resveratrol Potentiates Growth Inhibitory Effects of Rapamycin in<i>PTEN</i>-deficient Lipoma Cells by Suppressing p70S6 Kinase Activity

Leipert, Jenny; Kässner, Franziska; Schuster, Susanne; Händel, Norman; Körner, Antje; Kieß, Wieland; Garten, Antje

doi:10.1080/01635581.2016.1145244

Cited by 8 publications

(9 citation statements)

References 46 publications

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“…Our results indicate that Res shows no substantial effect on the mRNA level of PTEN in HCT116 cells, or the total protein level of PTEN. However, Res can apparently decrease the phosphorylation of PTEN, which is consistent with the previous studies that PTEN is involved in the anticancer effect of Res in cancer cells (45)(46)(47). To further unveil the relationship between BMP7 and PTEN, we introduced the BMP7 recombinant adenovirus and a specific antibody.…”

Section: Discussionsupporting

confidence: 62%

Resveratrol inactivates PI3K/Akt signaling through upregulating BMP7 in human colon cancer cells

et al. 2017

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Abstract. Colon cancer is common worldwide and accounts for the significant cancer related morbidity and mortality in patients. Although extensive advancement has been made in colon cancer treatment and diagnosis in the last decades, there is still a giant gap between the clinical expectation. It has been reported that resveratrol (Res) may be a potential candidate for cancer treatment. However, the specific mechanism underlying this activity remains unclear. In this study, we investigated the anticancer activity of Res in human colon cancer cells, and unveiled the possible mechanism for this effect. With cell viability, flow cytometry, PCR and western blot analysis, we demonstrated the efficacious anticancer activity of Res in HCT116 cells. Mechanically, we found that Res greatly upregulates BMP7 in HCT116 cells. Exogenous BMP7 enhances the anticancer effect of Res in HCT116 cells, which was almost reversed by the BMP7 specific antibody. Res does not activate the BMPs/Smads signaling, but decreases the phosphorylation of Akt1/2/3 substantially in HCT116 cells. Exogenous BMP7 enhances the inhibitory effect of Res on the phosphorylation of Akt1/2/3, while BMP7 immunodepletion reverses this effect notably. Res markedly decreases the phosphorylation of PTEN, which can be enhanced by exogenous BMP7 but partly reversed by the BMP7 antibody. Our findings suggested that Res may be a promising candidate for colon cancer treatment, and the anticancer activity may be mediated by inactivating PI3K/Akt signaling through upregulating BMP7 to decrease, at least, the phosphorylation of

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Section: Discussionsupporting

confidence: 62%

Resveratrol inactivates PI3K/Akt signaling through upregulating BMP7 in human colon cancer cells

et al. 2017

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“…It was previously shown that rapamycin upregulates Akt phosphorylation ( Leipert et al, 2016 ; O'Reilly et al, 2006 ; Schmid et al, 2014 ), which is already elevated in Pten cKO retinas ( Cantrup et al, 2012 ; Tachibana et al, 2016 ). We thus asked whether pAkt levels were further increased in animals treated with rapamycin.…”

Section: Resultsmentioning

confidence: 96%

“…Pten is a negative regulator of PI3K, and mTOR signalling is activated downstream of PI3K so, in the absence of PTEN, mTOR signalling is elevated ( O'Reilly et al, 2006 ). An open-label drug trial has been started with the mTOR inhibitor sirolimus (alternative name for rapamycin) to treat PHTS patients, and this drug has shown some efficacy in inhibiting the growth of lipomas, which are a type of hamartoma ( Leipert et al, 2016 ; Schmid et al, 2014 ; Wang et al, 2007 ). We previously reported that mTOR signalling is upregulated in Pten cKO retinas ( Cantrup et al, 2012 ).…”

Section: Resultsmentioning

confidence: 99%

“…The search for a pharmacological therapy requires the implementation of in vitro and, ideally, in vivo models for drug testing. One of the best in vitro models developed to date has been lipoma cell cultures derived from patients carrying germline mutations in PTEN , which are sensitive to sirolimus (the clinical name for rapamycin), which slows their growth ( Leipert et al, 2016 ; Schmid et al, 2014 ; Wang et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

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Generation of an animal model of Pten hamartoma tumour syndrome in the retina

Tachibana

Touahri

Dixit

et al. 2018

Disease Models &Amp; Mechanisms

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PTEN hamartoma tumour syndrome (PHTS) is a heterogeneous group of rare, autosomal dominant disorders associated with PTEN germline mutations. PHTS patients routinely develop hamartomas, which are benign tissue overgrowths comprised of disorganized ‘normal’ cells. Efforts to generate PHTS animal models have been largely unsuccessful due to the early lethality of homozygous germline mutations in Pten, together with the lack of hamartoma formation in most conditional mutants generated to date. We report herein a novel PHTS mouse model that reproducibly forms hamartoma-like lesions in the central retina by postnatal day 21. Specifically, we generated a Pten conditional knockout (cKO) using a retinal-specific Pax6::Cre driver that leads to a nearly complete deletion of Pten in the peripheral retina but produces a mosaic of ‘wild-type’ and Pten cKO cells centrally. Structural defects were only observed in the mosaic central retina, including in Müller glia and in the outer and inner limiting membranes, suggesting that defective mechanical integrity partly underlies the hamartoma-like pathology. Finally, we used this newly developed model to test whether rapamycin, an mTOR inhibitor that is currently the only PHTS therapy, can block hamartoma growth. When administered in the early postnatal period, prior to hamartoma formation, rapamycin reduces hamartoma size, but also induces new morphological abnormalities in the Pten cKO retinal periphery. In contrast, administration of rapamycin after hamartoma initiation fails to reduce lesion size. We have thus generated and used an animal model of retinal PHTS to show that, although current therapies can reduce hamartoma formation, they might also induce new retinal dysmorphologies.This article has an associated First Person interview with the first author of the paper.

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“…However, published studies on the role of mTOR in adipose tissue browning have been paradoxical. It is reported that Res influences mTOR complex 1 (mTORC1) or its downstream site P70S6 (16). In this study, we aimed to elucidate the role of Res in the formation of brown-like adipocytes in 3T3-L1 and explore mechanisms related to mTORC1 underlying this process.…”

mentioning

confidence: 99%

Resveratrol-induced brown fat-like phenotype in 3T3-L1 adipocytes partly via mTOR pathway

Liu¹,

Liao²,

Yin³

et al. 2020

Food & Nutrition Research

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Background: Browning of white adipose tissues (WAT) is recognized as a novel way to combat obesity and its related comorbidities. Thus, a lot of dietary agents contributing to browning of WAT have been identified. Objective: In this study, we try to explore the mechanism of the browning of WAT induced by resveratrol (Res) in 3T3-L1 adipocytes. Methods: The levels of cell viability and lipid accumulation were evaluated under different concentrations of Res. Cell signaling pathway analysis was performed to investigate the possible mechanisms of the WAT browning effect of Res in 3T3-L1 cells. Results: We found that Res induced the brown fat-like phenotype by activating protein expressions of brown adipocyte-specific markers, such as peroxisome proliferator-activated receptor gamma (PPAR-γ), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), and uncoupling protein 1 (UCP1). Besides, Res reduced lipid accumulation, as shown by Oil Red O staining. The increased small lipid droplets implied that Res-treated 3T3-L1 adipocytes had some features of brown adipocytes. The brown fat-like phenotype in 3T3-L1 adipocytes induced by Res was possibly mediated by activation of mammalian target of rapamycin (mTOR), as brown adipocyte-specific markers were decreased by rapamycin, an inhibitor of mTOR and the MHY1485 treatment, an activator of mTOR, showed the similar effect of Res on browning markers. Conclusions: Res induced brown-like adipocyte phenotype in 3T3-L1 adipocytes partly via mTOR pathway, which provided new insights into the utilization of Res to prevent obesity and related comorbidities.

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Resveratrol Potentiates Growth Inhibitory Effects of Rapamycin inPTEN-deficient Lipoma Cells by Suppressing p70S6 Kinase Activity

Cited by 8 publications

References 46 publications

Resveratrol inactivates PI3K/Akt signaling through upregulating BMP7 in human colon cancer cells

Resveratrol inactivates PI3K/Akt signaling through upregulating BMP7 in human colon cancer cells

Generation of an animal model of Pten hamartoma tumour syndrome in the retina

Resveratrol-induced brown fat-like phenotype in 3T3-L1 adipocytes partly via mTOR pathway

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