scholarly journals Metformin and JQ1 synergistically inhibit obesity-activated thyroid cancer

2018 ◽  
Vol 25 (10) ◽  
pp. 865-877 ◽  
Author(s):  
Sunmi Park ◽  
Mark C Willingham ◽  
Jun Qi ◽  
Sheue-Yann Cheng
Keyword(s):  
Thyroid Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Cancer Progression ◽  
High Fat Diet ◽  
Combined Treatment ◽  
Thyroid Tumor ◽  
Molecular Evidence ◽  
Strong Positive Correlation ◽  
High Fat

Compelling epidemiological evidence shows a strong positive correlation of obesity with thyroid cancer.In vivostudies have provided molecular evidence that high-fat-diet-induced obesity promotes thyroid cancer progression by aberrantly activating leptin-JAK2-STAT3 signaling in a mouse model of thyroid cancer (ThrbPV/PVPten+/−mice). TheThrbPV/PVPten+/−mouse expresses a dominantly negative thyroid hormone receptor β (denoted as PV) and a deletion of one single allele of thePtengene. TheThrbPV/PVPten+/−mouse spontaneously develops follicular thyroid cancer, which allows its use as a preclinical mouse model to test potential therapeutics. We recently showed that inhibition of STAT3 activity by a specific inhibitor markedly delays thyroid cancer progression in high-fat-diet-induced obeseThrbPV/PVPten+/−mice (HFD-ThrbPV/PVPten+/−mice). Further, metformin, a widely used antidiabetic drug, blocks invasion and metastasis, but not thyroid tumor growth in HFD-ThrbPV/PVPten+/−mice. To improve efficacy in reducing thyroid tumor growth, we treated HFD-ThrbPV/PVPten+/−with JQ1, a potent inhibitor of the activity of bromodomain and extraterminal domain (BET) and with metformin. We found that the combined treatment synergistically suppressed thyroid tumor growth by attenuating STAT3 and ERK signaling, resulting in decreased anti-apoptotic key regulators such as Mcl-1, Bcl-2 and survivin and increased pro-apoptotic regulators such as Bim, BAD and cleave caspase 3. Furthermore, combined treatment of JQ1 and metformin reduced cMyc protein levels to suppress vascular invasion, anaplasia and lung metastasis. These findings indicate that combined treatment is more effective than metformin alone and suggest a novel treatment modality for obesity-activated thyroid cancer.

scholarly journals Inhibition of mTORC1 signaling reduces tumor growth but does not prevent cancer progression in a mouse model of thyroid cancer

2010 ◽  
Vol 31 (7) ◽  
pp. 1284-1291 ◽  
Author(s):  
Celine J. Guigon ◽  
Laura Fozzatti ◽  
Changxue Lu ◽  
Mark C. Willingham ◽  
Sheue-yann Cheng
Keyword(s):  
Thyroid Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Mtorc1 Signaling

scholarly journals Diet-Induced Obesity Increases Tumor Growth and Promotes Anaplastic Change in Thyroid Cancer in a Mouse Model

Endocrinology ◽  
2013 ◽  
Vol 154 (8) ◽  
pp. 2936-2947 ◽  
Author(s):  
Won Gu Kim ◽  
Jeong Won Park ◽  
Mark C. Willingham ◽  
Sheue-yann Cheng
Keyword(s):  
Thyroid Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
Thyroid Tumor ◽  
Janus Kinase ◽  
Histopathological Analysis ◽  
Diet Induced Obesity ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Recent epidemiological studies provide strong evidence suggesting obesity is a risk factor in several cancers, including thyroid cancer. However, the molecular mechanisms by which obesity increases the risk of thyroid cancer are poorly understood. In this study, we evaluated the effect of diet-induced obesity on thyroid carcinogenesis in a mouse model that spontaneously develops thyroid cancer (ThrbPV/PVPten+/− mice). These mice harbor a mutated thyroid hormone receptor-β (denoted as PV) and haplodeficiency of the Pten gene. A high-fat diet (HFD) efficiently induced the obese phenotype in ThrbPV/PVPten+/− mice after 15 weeks. Thyroid tumor growth was markedly greater and survival was significantly lower in ThrbPV/PVPten+/− mice fed an HFD than in controls fed a low-fat diet (LFD). The HFD increased thyroid tumor cell proliferation by increasing the protein levels of cyclin D1 and phosphorylated retinoblastoma protein to propel cell cycle progression. Histopathological analysis showed that the frequency of anaplasia of thyroid cancer was significantly greater (2.6-fold) in the HFD group than the LFD group. The HFD treatment led to an increase in parametrial/epididymal fat pad and elevated serum leptin levels in ThrbPV/PVPten+/− mice. Further molecular analyses indicated that the HFD induced more aggressive pathological changes that were mediated by increased activation of the Janus kinase 2-signaling transducer and activator of transcription 3 (STAT3) signaling pathway and induction of STAT3 target gene expression. Our findings demonstrate that diet-induced obesity exacerbates thyroid cancer progression in ThrbPV/PVPten+/− mice and suggest that the STAT3 signaling pathway could be tested as a potential target for the treatment of thyroid cancer.

scholarly journals Inhibition of STAT3 activity delays obesity-induced thyroid carcinogenesis in a mouse model

2015 ◽  
Vol 23 (1) ◽  
pp. 53-63 ◽  
Author(s):  
Jeong Won Park ◽  
Cho Rong Han ◽  
Li Zhao ◽  
Mark C Willingham ◽  
Sheue-yann Cheng
Keyword(s):  
Thyroid Cancer ◽  
Mouse Model ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Specific Inhibitor ◽  
Epidemiologic Studies ◽  
Thyroid Tumor ◽  
Obesity Prevalence ◽  
Marked Rise ◽  
Mesenchymal Transition

Compelling epidemiologic studies indicate that obesity is a risk factor for many human cancers, including thyroid cancer. In recent decades, the incidence of thyroid cancer has dramatically increased along with a marked rise in obesity prevalence. We previously demonstrated that a high fat diet (HFD) effectively induced the obese phenotype in a mouse model of thyroid cancer (ThrbPV/PVPten+/− mice). Moreover, HFD activates the STAT3 signal pathway to promote more aggressive tumor phenotypes. The aim of the present study was to evaluate the effect of S3I-201, a specific inhibitor of STAT3 activity, on HFD-induced aggressive cancer progression in the mouse model of thyroid cancer. WT and ThrbPV/PVPten+/− mice were treated with HFD together with S3I-201 or vehicle-only as controls. We assessed the effects of S3I-201 on HFD-induced thyroid cancer progression, the leptin-JAK2-STAT3 signaling pathway, and key regulators of epithelial-mesenchymal transition (EMT). S3I-201 effectively inhibited HFD-induced aberrant activation of STAT3 and its downstream targets to markedly inhibit thyroid tumor growth and to prolong survival. Decreased protein levels of cyclins D1 and B1, cyclin dependent kinase 4 (CDK4), CDK6, and phosphorylated retinoblastoma protein led to the inhibition of tumor cell proliferation in S3I-201-treated ThrbPV/PVPten+/− mice. Reduced occurrence of vascular invasion and blocking of anaplasia and lung metastasis in thyroid tumors of S3I-201-treated ThrbPV/PVPten+/− mice were mediated via decreased expression of vimentin and matrix metalloproteinases, two key effectors of EMT. The present findings suggest that inhibition of the STAT3 activity would be a novel treatment strategy for obesity-induced thyroid cancer.

Sex differences in response to a high fat diet in an Alzheimer’s Disease mouse model

2018 ◽  
Author(s):  
Alejandra Freire Fernández-Regatillo ◽  
María L. de Ceballos ◽  
Jesús Argente ◽  
Sonia Díaz Pacheco ◽  
Clara González Martínez
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sex Differences ◽  
Mouse Model ◽  
High Fat Diet ◽  
High Fat

Blood Flow Improvement Effect of Bokbunja (Rubus coreanus) Seed Oil in High-Fat Diet-Fed Mouse Model

2015 ◽  
Vol 44 (8) ◽  
pp. 1105-1113
Author(s):  
Hyelin Jeon ◽  
Sungmin Kwak ◽  
Su-Jin Oh ◽  
Hyun Soo Nam ◽  
Doo Won Han ◽  
...  
Keyword(s):  
Blood Flow ◽  
Mouse Model ◽  
High Fat Diet ◽  
Seed Oil ◽  
High Fat ◽  
Rubus Coreanus ◽  
Improvement Effect ◽  
Flow Improvement
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