PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mrow><mml:mi mathvariant="bold">γ</mml:mi></mml:mrow></mml:math>Promotes Growth and Invasion of Thyroid Cancer Cells

Wood, William M.; Sharma, Vibha; Bauerle, Kevin T.; Pike, Laura A.; Zhou, Qiong; Fretwell, Deborah; Schweppe, Rebecca E.; Haugen, Bryan R.

doi:10.1155/2011/171765

Cited by 29 publications

(24 citation statements)

References 40 publications

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“…Furthermore, DTC cell lines and primary PTC tumors have high endogenous TXNIP levels, whereas TXNIP expression is low or absent in ATC cell lines and primary tumor specimens. This TXNIP expression pattern is opposite to what we previously reported with PPARγ, which is highly expressed in ATC cell lines and absent in DTC cell lines and whose forced expression confers a more aggressive phenotype in thyroid cancer cells in vitro and in vivo [4]. These data are consistent with a previously published report that TXNIP is a negatively-regulated target of PPARγ [29].…”

Section: Discussionsupporting

confidence: 75%

Thioredoxin interacting protein (TXNIP) is a novel tumor suppressor in thyroid cancer

et al. 2014

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BackgroundThyroid cancer is the most common endocrine malignancy, and many patients with metastatic differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC) fail to respond to conventional therapies, resulting in morbidity and mortality. Additional therapeutic targets and treatment options are needed for these patients. We recently reported that peroxisome proliferator-activated receptor gamma (PPARγ) is highly expressed in ATC and confers an aggressive phenotype when overexpressed in DTC cells.MethodsMicroarray analysis was used to identify downstream targets of PPARγ in ATC cells. Western blot analysis and immunohistochemistry (IHC) were used to assess thioredoxin interacting protein (TXNIP) expression in thyroid cancer cell lines and primary tumor specimens. Retroviral transduction was used to generate ATC cell lines that overexpress TXNIP, and assays that assess glucose uptake, viable cell proliferation, and invasion were used to characterize the in vitro properties of these cells. An orthotopic thyroid cancer mouse model was used to assess the effect of TXNIP overexpression in ATC cell lines in vivo.ResultsUsing microarray analysis, we show that TXNIP is highly upregulated when PPARγ is depleted from ATC cells. Using Western blot analysis and IHC, we show that DTC and ATC cells exhibit differential TXNIP expression patterns. DTC cell lines and patient tumors have high TXNIP expression in contrast to low or absent expression in ATC cell lines and tumors. Overexpression of TXNIP decreases the growth of HTh74 cells compared to vector controls and inhibits glucose uptake in the ATC cell lines HTh74 and T238. Importantly, TXNIP overexpression in T238 cells results in attenuated tumor growth and decreased metastasis in an orthotopic thyroid cancer mouse model.ConclusionsOur findings indicate that TXNIP functions as a tumor suppressor in thyroid cells, and its downregulation is likely important in the transition from differentiated to advanced thyroid cancer. These studies underscore the potential of TXNIP as a novel therapeutic target and prognostic indicator in advanced thyroid cancer.

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Section: Discussionsupporting

confidence: 75%

Thioredoxin interacting protein (TXNIP) is a novel tumor suppressor in thyroid cancer

et al. 2014

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“…For the orthotopic murine model, BCPAP and 8505C cells (5 × 10 5 in 5 µL) engineered to express a luciferase-IRES-GFP plasmid were injected into the right thyroid lobe of athymic nude mice (Harlan: Athymic Nude-Foxn1 nu ; female, 6–8 week old), as previously described (9,22). Tumor establishment and progression was measured weekly by detection of bioluminescence with the Xenogen IVIS200 system (Caliper) in the University of Colorado Cancer Center (UCCC) Small Animal Imaging Core.…”

Section: Methodsmentioning

confidence: 99%

FAK Expression, Not Kinase Activity, Is a Key Mediator of Thyroid Tumorigenesis and Protumorigenic Processes

Kessler

Sharma

Zhou

et al. 2016

Molecular Cancer Research

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There are limited therapy options for advanced thyroid cancer, including papillary and anaplastic thyroid cancer (PTC and ATC). Focal Adhesion Kinase (FAK) regulates cell signaling by functioning as a scaffold and kinase. Previously we demonstrated that FAK is overexpressed and activated in thyroid cancer cells and human PTC clinical specimens. However, it remains unclear whether patients with advanced thyroid cancer will benefit from FAK inhibition. Therefore, the dual functions of FAK in mediating pro-tumorigenic processes and thyroid tumorigenesis were investigated. Evidence here shows that FAK expression predominantly regulates thyroid cancer cell growth, viability, and anchorage-independent growth. FAK inhibition, with PF-562,271 treatment, modestly reduced tumor volumes, while FAK depletion, through shRNA knockdown, significantly reduced tumor volumes in vivo. A role for FAK expression in tumor establishment was demonstrated in a model of PTC, where FAK knockdown tumors did not develop. FAK depletion also led to a significant decrease in overall metastatic burden. Interestingly, pretreatment with a FAK inhibitor resulted in a paradoxical increase in metastasis in a model of ATC, but decreased metastasis in a model of PTC. These data provide the first evidence that FAK expression is critical for the regulation of thyroid tumorigenic functions.

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“…BCPAP and 8505C cells (5 × 10 5 ) engineered to express a luciferase-IRES-GFP plasmid were injected into the right thyroid lobe of nude mice, as previously described (28-30). Briefly, male athymic nude mice (NCI; ~30 grams; 10–12 weeks old) were anesthetized with tribromoethanol (250 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

Targeted Inhibition of Src Kinase with Dasatinib Blocks Thyroid Cancer Growth and Metastasis

Chan

Xia

Pike

et al. 2012

Clinical Cancer Research

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Purpose There are no effective therapies for patients with poorly differentiated papillary thyroid cancer (PTC) or anaplastic thyroid cancer (ATC), and metastasis to the bone represents a significantly worse prognosis. Src family kinases (SFKs) are overexpressed and activated in numerous tumor types and have emerged as a promising therapeutic target, especially in relation to metastasis. We recently showed that Src is overexpressed and activated in thyroid cancer. We therefore tested whether inhibition of Src with dasatinib (BMS-354825) blocks thyroid cancer growth and metastasis. Experimental Design The effects of dasatinib on thyroid cancer growth, signaling, cell cycle, and apoptosis were evaluated in vitro. The therapeutic efficacy of dasatinib was further tested in vivo using an orthotopic and a novel experimental metastasis model. Expression and activation of SFKs in thyroid cancer cells was characterized, and selectivity of dasatinib was determined using an Src gatekeeper mutant. Results Dasatinib treatment inhibited Src signaling, decreased growth, and induced cell-cycle arrest and apoptosis in a subset of thyroid cancer cells. Immunoblotting showed that c-Src and Lyn are expressed in thyroid cancer cells and that c-Src is the predominant SFK activated. Treatment with dasatinib blocked PTC tumor growth in an orthotopic model by more than 90% (P = 0.0014). Adjuvant and posttreatment approaches with dasatinib significantly inhibited metastasis (P = 0.016 and P = 0.004, respectively). Conclusion These data provide the first evidence that Src is a central mediator of thyroid cancer growth and metastasis, indicating that Src inhibitors may have a higher therapeutic efficacy in thyroid cancer, as both antitumor and antimetastatic agents.

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PPARγPromotes Growth and Invasion of Thyroid Cancer Cells

Cited by 29 publications

References 40 publications

Thioredoxin interacting protein (TXNIP) is a novel tumor suppressor in thyroid cancer

Thioredoxin interacting protein (TXNIP) is a novel tumor suppressor in thyroid cancer

FAK Expression, Not Kinase Activity, Is a Key Mediator of Thyroid Tumorigenesis and Protumorigenic Processes

Targeted Inhibition of Src Kinase with Dasatinib Blocks Thyroid Cancer Growth and Metastasis

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