5´-AMP-activated Protein Kinase (AMPK) Regulates Papillary (TPC-1 and BCPAP) Thyroid Cancer Cell Survival, Migration, Invasion and Epithelial-to-Mesenchymal Transition.

5´-AMP-activated Protein Kinase (AMPK) Regulates Papillary (TPC-1 and BCPAP) Thyroid Cancer Cell Survival, Migration, Invasion and Epithelial-to-Mesenchymal Transition.

Thyroid. 2016 Apr 27;

Authors: Cazarin JM, Coelho RG, Hecht F, Andrade BM, Carvalho DP

Abstract
BACKGROUND: Differentiated thyroid carcinomas (DTC) are associated with a good prognosis and a high survival rate. However, tumor recurrence occurs in approximately 20% to 30% of DTC patients, reinforcing the importance of identifying new molecular targets for cancer management. We have shown that the 5´-AMP-activated protein kinase (AMPK) is over-activated in papillary thyroid cancer (PTC). In this study, we aimed to investigate the effects of AICAR, an AMPK activator, on various aspects of thyroid cancer cell behavior, including cell survival, apoptosis, migration, invasion and epithelial-to-mesenchymal transition (EMT), in the human thyroid cancer cell lines BCPAP and TPC-1.
METHODS: BCPAP and TPC-1 cells were cultivated in DMEM, and the non-tumor-derived cell line Nthy-ORI was grown in RPMI. Cells were treated or not with AICAR for different periods of time. We analyzed the cell growth rate, cell cycle phase, apoptosis, cell migration and invasion using Transwell inserts, and EMT was quantified by the expression of mesenchymal and epithelial markers.
RESULTS: AMPK is activated in thyroid cancer cell lines and AICAR treatment further increased AMPK phosphorylation. After 48 h of AICAR treatment, the percentage of cells in the G2/M phase decreased and a G0/G1-phase arrest was induced in all of the cells. AMPK activation effectively induced apoptosis in the BCPAP and TPC-1 cancer cell lines, while no apoptosis induction was observed in Nthy-ORI. AICAR also reduced the migration of Nthy-ORI and BCPAP cells by 30% and approximately 60% in TPC-1 cells. AICAR had no effect on cell invasion in Nthy-ORI and TPC-1 cells, but a significant reduction of cell invasion was observed in BCPAP cells. AICAR induced a significant reduction of N-cadherin and no changes in the expression of vimentin or TCF/Zeb1 protein in BCPAP cells. No differences in the expression of EMT markers were found in the AICAR-treated NTHY-ORI cells. A remarkable reduction of vimentin, TCF/Zeb1 and N-cadherin protein expression was detected in the TPC-1 cells.
CONCLUSIONS: Increased activation of AMPK in PTC cell lines leads to a strong anti-tumor response, as measured by the inhibition of cell proliferation, cell migration and induction of cell death. We also demonstrate that AMPK activation reverses EMT in TPC-1 cells.

PMID: 27121619 [PubMed - as supplied by publisher]

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