FROM NUCLEUS TO MITOCHONDRIA: INSIGHTS INTO THE ROLE OF TERT IN THE PROGRESSION OF PAPILLARY THYROID CARCINOMA

TERT is the protein component of the telomerase holoenzyme and has been reported overexpressed in many cancer types. The most studied role for TERT in cancer is the regeneration of telomeres allowing the avoidance of senescence and, in turn, the continued proliferation of cancerous cells. Recent works have identified roles for the TERT protein in cellular compartments outside the nucleus, in particular in mitochondria, with a protective role against endogenous and therapy-induced oxidative stress (OS). Papillary thyroid cancers (PTCs) have a generally good prognosis but a small subset of cases can dedifferentiate and become more resistant to radioiodine used as a first-line treatment in cases of metastatic PTCs, a trait often found in TERT promoter mutated cases, significantly reducing survival rates. In this work we aimed to study the role of TERT extra-nuclear localization in the progression of PTC. We assessed TERT nuclear export, resistance to OS and proliferative properties in the K1 papillary thyroid cancer immortalized cell line model transfected with wild-type TERT and specific TERT plasmid constructs that limit its localization to the nucleus (TERT-nuc) or to the mitochondria (TERT-mito). Moreover, we investigated the effect of PP2, a SRC kinase inhibitor, which is supposed to inhibit the pathway that allows for TERT nuclear export, on K1 cell proliferation. We found that TERT shuttled into the cytoplasm and in some cases to the mitochondria in response to OS increase either from H2O2 or the BRAF inhibitor PLX4720. Tangentially to our experiments, we proved that mitochondrial TERT is able to reduce mitochondrial OS under H2O2 challenge and to induce mitochondrial fragmentation. Finally, we saw that K1 cells transfected with the TERT-nuc plasmid or treated with PP2 had a reduced proliferative advantage. In conclusion, we provide insights into the involvement of mitochondrial TERT in OS response and therapy-induced stress resistance and that by limiting TERT mitochondrial localization by inhibition of SRC kinase, involved in TERT nuclear export, may represent an interesting solution to therapeutic resistant PTCs.