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1.
The Korean Journal of Internal Medicine ; : 474-481, 2014.
Artículo en Inglés | WPRIM | ID: wpr-116730

RESUMEN

BACKGROUND/AIMS: 5'-Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a cellular energy sensor that monitors intracellular AMP/adenosine triphosphate (ATP) ratios and is a key regulator of the proliferation and survival of diverse malignant cell types. In the present study, we investigated the effect of activating AMPK by 5-aminoimidazole-4-carboxamide-ribonucleotide (AICAR) in thyroid cancer cells. METHODS: We used FRO thyroid cancer cells harboring the BRAF(V600E) mutation to examine the effect of AICAR on cell proliferation and cell survival. We also evaluated the involvement of mitogen-activated protein kinase (MAPK) pathways in this effect. RESULTS: We found that AICAR treatment promoted AMPK activation and suppressed cell proliferation and survival by inducing p21 accumulation and activating caspase-3. AICAR significantly induced activation of p38 MAPK, and pretreatment with SB203580, a specific inhibitor of the p38 MAPK pathway, partially but significantly rescued cell survival. Furthermore, small interfering RNA targeting AMPK-alpha1 abolished AICAR-induced activation of p38 MAPK, p21 accumulation, and activation of caspase-3. CONCLUSIONS: Our findings demonstrate that AMPK activation using AICAR inhibited cell proliferation and survival by activating p38 MAPK and proapoptotic molecules in FRO thyroid cancer cells. These results suggest that the AMPK and p38 MAPK signaling pathways may be useful therapeutic targets to treat thyroid cancer.


Asunto(s)
Humanos , Proteínas Quinasas Activadas por AMP/genética , Aminoimidazol Carboxamida/análogos & derivados , Antineoplásicos/farmacología , Caspasa 3/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Relación Dosis-Respuesta a Droga , Activación Enzimática , Activadores de Enzimas/farmacología , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Interferencia de ARN , Ribonucleótidos/farmacología , Transducción de Señal/efectos de los fármacos , Neoplasias de la Tiroides/enzimología , Factores de Tiempo , Transfección , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores
2.
Korean Journal of Medicine ; : 509-517, 2010.
Artículo en Coreano | WPRIM | ID: wpr-219496

RESUMEN

BACKGROUND/AIMS: Hypothyroidism has been reported in 36~85% of patients treated with sunitinib for renal cell carcinoma or gastrointestinal stromal tumor. However, the mechanism behind this hypothyroidism is unclear. This study evaluated the effects of sunitinib, a multi-target tyrosine kinase inhibitor, on the survival and proliferation of thyrocytes using FRTL-5 rat thyroid cells. METHODS: We examined the effect of sunitinib on cell proliferation in the presence and absence of thyroid stimulating hormone (TSH) in a colorimetric assay. Effects on the cell cycle were evaluated by flow cytometry, and on apoptosis using an annexin V apoptosis assay kit and by immunoblotting for caspase-3. Immunoblotting was also used to evaluate changes in the levels of intracellular proteins associated with the G1-S phase of the cell cycle. RESULTS: Sunitinib suppressed the proliferation of FRTL-5 cells in a dose- and time-dependent manner. This suppressive effect was enhanced by the presence of TSH (1 mU/mL). Sunitinib was subsequently shown, in flow cytometric analyses, to arrest the cell cycle at the G1-S phase. Furthermore, it induced apoptosis at a high concentration (15 micrometer) by activating caspase-3. G1-S phase arrest was associated with the induction of p27(kip1) and p21(cip1), whose expression is suppressed by TSH under control conditions. Sunitinib also decreased intracellular levels of cyclin D1 and cyclin-dependent kinase 2 in FRTL-5 cells. CONCLUSIONS: Sunitinib induced apoptosis in and suppressed the proliferation of FRTL-5 cells. Its suppression of proliferation was further enhanced by the presence of TSH. Sunitinib arrested the cell cycle in the G1-S phase by inducing the expression of p27(kip1)/p21(cip1), which are suppressed by TSH under normal conditions. Collectively, these findings suggest that sunitinib may interfere with TSH signaling pathways in normal thyrocytes.


Asunto(s)
Animales , Humanos , Ratas , Anexina A5 , Apoptosis , Carcinoma de Células Renales , Caspasa 3 , Ciclo Celular , Proliferación Celular , Ciclina D1 , Quinasa 2 Dependiente de la Ciclina , Citometría de Flujo , Tumores del Estroma Gastrointestinal , Hipotiroidismo , Immunoblotting , Indoles , Proteínas Tirosina Quinasas , Proteínas , Pirroles , Glándula Tiroides , Tirotropina
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