LATS Young Investigator Awards


Juliana Cazarin

Winner 2013


POTENTIAL ANTI-TUMORIGENIC EFFECTS OF AMP- KINASE (AMPK) ON PAPILLARY THYROID TUMOR CELL LINEAGES

Category: Basic Research
In the last few years several in vitro studies have shown that AMPK regulates diverse cellular processes involved in carcinogenesis as cell growth, apoptosis, autophagy and cell polarity (Luo et al, 2012). The role of AMPK in carcinogenesis seems to be related to two opposing functions: (1) promotion of tumor cells survival in unfavorable metabolic situations, (2) decrease in cell proliferation. We recently described that AMPK activation decreases iodine uptake and stimulates glucose uptake in rat thyrocytes (Andrade et al, 2011, Andrade et al., 2012), two changes that are also observed in thyroid tumor progression. However, the role of AMPK in thyroid cancer is not known.

Objective: Evaluate, in vitro, the role of AMPK on cellular processes involved in thyroid carcinogenesis.

Methods: Normal human thyrocyte lineage (NTHY-ORI) and two papillary thyroid carcinoma lineages BCPAP (BRAF v600e mutation) and TPC-1 (RET/PTC translocation) were treated with the pharmacological activator of AMPK, AICAR (1mM) for 24h. AMPK expression, cell proliferation, cell adhesion, cell migration and cell cycle were evaluated.

Results: Total and phosphorylated AMPK are expressed in the 3 different cell lineages. However, the basal expression of phosphorylated AMPK is higher in BCPAP.
We observed a quite similar reduction in cell number of the 3 lineages after Aicar treatment for 24h. When the cell cycle was evaluated under the same experimental conditions we observed a reduction of cell proliferation with a G0/G1 phase arrest in NTHY-ORI and G0/G1 and S phase arrest in BCPAP.
In TPC-1 cells, we could not observe reduction of cell proliferation.
Aicar also produced an increase in cell adhesion and a reduced cell migration ability in all the three lineages.

Conclusion: AMPK activation reduces cell proliferation in the normal thyrocyte cell lineage NTHY and in the papillary carcinoma cell lineage BCPAP. We could not observe a reduction of cell proliferation in the papillary carcinoma cell lineage TPC-1 upon AMPK activation. However, we observed a reduction in TPC-1 cell number under the same conditions.
We also demonstrated an increase in cell adhesion and reduction of cell migration ability, which may be related to a reduced metastatic ability and, consequently, a less aggressive phenotype.
These data strongly suggests a potencial anti-tumorigenic effect of AMPK activation on papillary thyroid tumor cells lineages, in vitro.

Bibliographical references:
Andrade BM, Araujo RL, Perry RLS, Souza ECL, Cazarin JM, Carvalho DP, Ceddia, RB A novel role for AMP-kinase in the regulation of the Na+/I--symporter and iodide uptake in the rat thyroid gland. Am J Physiol Cell Physiol, 2011.
Andrade BM, Cazarin J, Zancan P, Carvalho DP. AMP-Activated Protein Kinase Upregulates Glucose Uptake in Thyroid PCCL3 Cells Independent of Thyrotropin. Thyroid, 2012.
Luo Z, Zang M, Guo W. AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncol., 6(3): 457–470, 2010