Perspectives of the AMP-activated kinase (AMPK) signalling pathway in thyroid cancer

Abstract

Approximately 90% of non-medullary thyroid malignancies originate from the follicular cell and are classified as papillary or follicular (well-differentiated) thyroid carcinomas, showing an overall favourable prognosis. However, recurrence or persistence of the disease occurs in some cases associated with the presence of loco-regional or distant metastatic lesions that generally become resistant to radioiodine therapy, while glucose uptake and metabolism are increased. Recent advances in the field of tumor progression have shown that CTC (circulating tumour cells) are metabolic and genetically heterogeneous. There is now special interest in unravelling the mechanisms that allow the reminiscence of dormant tumour lesions that might be related to late disease progression and increased risk of recurrence. AMPK (AMP-activated protein kinase) is activated by the depletion in cellular energy levels and allows adaptive changes in cell metabolism that are fundamental for cell survival in a stressful environment; nevertheless, the activation of this kinase also decreases cell proliferation rate and induces tumour cell apoptosis. In the thyroid field, AMPK emerged as a novel important intracellular pathway, since it regulates both iodide and glucose uptakes in normal thyroid cells. Furthermore, it has recently been demonstrated that the AMPK pathway is highly activated in papillary thyroid carcinomas, although the clinical significance of these findings remains elusive. Herein we review the current knowledge about the role of AMPK activation in thyroid physiology and pathophysiology, with special focus on thyroid cancer.

Keywords: AMPK; NIS; Warburg effect; mTOR; metformin; thyroid cancer.

Figure 1. Schematic representation of AMPK subunits α,β,γ

Allosteric activation of AMPK occurs through an increase in the intracellular AMP/ATP ratio that allows upstream kinases such as LKB1 (liver kinase B1), TAK1 (TGF-β-activated kinase 1) or CAMKKβ (Calmodulin kinase kinase β) to phosphorylate Thr¹⁷² in AMPK α-catalytic subunit. Some drugs are also able to directly or indirectly activate AMPK. Once activated, AMPK inhibits ATP-consuming process and stimulates ATP synthesis pathways. In the normal thyroid, iodide uptake decreases and glucose uptake increases by AMPK activation.