The effect of 5-aminoimidazole-4-carboxamideribonucleoside was mediated by p38 mitogen activated protein kinase signaling pathway in FRO thyroid cancer cells
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Background/Aims: 5′-Adenosine monophosphate (AMP)-activated protein kinase(AMPK) is a cellular energy sensor that monitors intracellular AMP/adenosinetriphosphate (ATP) ratios and is a key regulator of the proliferation and survivalof diverse malignant cell types. In the present study, we investigated the effect ofactivating AMPK by 5-aminoimidazole-4-carboxamide-ribonucleotide (AICAR) inthyroid cancer cells. Methods: We used FRO thyroid cancer cells harboring the BRAFV600E mutation toexamine the effect of AICAR on cell proliferation and cell survival. We also evaluatedthe involvement of mitogen-activated protein kinase (MAPK) pathways inthis effect. Results: We found that AICAR treatment promoted AMPK activation and suppressedcell proliferation and survival by inducing p21 accumulation and activatingcaspase-3. AICAR significantly induced activation of p38 MAPK, and pretreatmentwith SB203580, a specific inhibitor of the p38 MAPK pathway, partially butsignificantly rescued cell survival. Furthermore, small interfering RNA targetingAMPK-α1 abolished AICAR-induced activation of p38 MAPK, p21 accumulation,and activation of caspase-3. Conclusions: Our findings demonstrate that AMPK activation using AICAR inhibitedcell proliferation and survival by activating p38 MAPK and proapoptoticmolecules in FRO thyroid cancer cells. These results suggest that the AMPK andp38 MAPK signaling pathways may be useful therapeutic targets to treat thyroidcancer.
Abstract
Background/Aims: 5′-Adenosine monophosphate (AMP)-activated protein kinase(AMPK) is a cellular energy sensor that monitors intracellular AMP/adenosinetriphosphate (ATP) ratios and is a key regulator of the proliferation and survivalof diverse malignant cell types. In the present study, we investigated the effect ofactivating AMPK by 5-aminoimidazole-4-carboxamide-ribonucleotide (AICAR) inthyroid cancer cells. Methods: We used FRO thyroid cancer cells harboring the BRAFV600E mutation toexamine the effect of AICAR on cell proliferation and cell survival. We also evaluatedthe involvement of mitogen-activated protein kinase (MAPK) pathways inthis effect. Results: We found that AICAR treatment promoted AMPK activation and suppressedcell proliferation and survival by inducing p21 accumulation and activatingcaspase-3. AICAR significantly induced activation of p38 MAPK, and pretreatmentwith SB203580, a specific inhibitor of the p38 MAPK pathway, partially butsignificantly rescued cell survival. Furthermore, small interfering RNA targetingAMPK-α1 abolished AICAR-induced activation of p38 MAPK, p21 accumulation,and activation of caspase-3. Conclusions: Our findings demonstrate that AMPK activation using AICAR inhibitedcell proliferation and survival by activating p38 MAPK and proapoptoticmolecules in FRO thyroid cancer cells. These results suggest that the AMPK andp38 MAPK signaling pathways may be useful therapeutic targets to treat thyroidcancer.
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