Endocrine Abstracts

TERT is the protein component of the telomerase enzyme and is overexpressed in many cancer types. The most well-known role for TERT is the regeneration of telomeres allowing the avoidance of senescence and the continued proliferation of stem and cancer cells. Recent studies have identified other roles for TERT in compartments outside the nucleus, in particular in mitochondria, with a protective role against endogenous and therapy-induced oxidative stress (OS). A small subset of papillary thyroid cancers (PTCs) may dedifferentiate and become resistant to radio-iodine therapy, a trait often found in TERT promoter mutated cases, significantly reducing overall survival rates. We aimed to study the role of TERT extra-nuclear localization in the progression of PTC. For this purpose, we studied TERT nuclear export by confocal immunofluorescence, resistance to OS with specific fluorescent probes and proliferative properties with WST-8 in the K1 papillary thyroid cancer immortalized cell line transfected with wild-type TERT and specific TERT constructs that limit its localization to the nucleus (TERT-nuc) or to the mitochondria (TERT-mito). Moreover, we investigated the effect of SRC kinase inhibitor PP2, which reduces TERT nuclear exit, on K1 cell proliferation. We found that TERT shuttled into the cytoplasm and partly to the mitochondria in response to OS increase either from H2O2 or the BRAF inhibitor PLX4720. Moreover, we proved that mitochondrial TERT is able to reduce mitochondrial OS under H2O2 challenge and to induce mitochondrial fragmentation. Finally, we demonstrated that K1 cells transfected with the TERT-nuc or treated with PP2 had a reduced proliferative advantage compared to those transfected with wild-type TERT and untreated cells, respectively. In conclusion, we provide insights into the involvement of mitochondrial TERT in OS response and, for the first time, in BRAF inhibitor therapy-induced stress resistance. These data, which will be extended to other thyroid cancer subtypes, suggest that disrupting TERT mitochondrial localization by inhibition of SRC kinase, involved in TERT nuclear export, may represent an effective solution to therapeutic resistant PTCs.