Molecular mechanisms of action in TSH-mediated regulation of thyroid cancer cells. Role of PKC

ROSEMBLIT C; DIAZ-FLAQUÉ MC; DÍAZ ALBUJA JA; BARREIRO ARCOS ML; CAYROL MF; STERLE HA; DEBERNARDI MM; PAULAZO MA; KLECHA A; CREMASCHI GA

Congreso; Reunion Conjunta de Sociedades de Biociencias 2019; 2019

The incidenceof thyroid cancer has increased significantly within last decades in Argentinaas in the rest of the world. Thyroid stimulating hormone (TSH) controls thyroidfunction by binding to TSH receptor (TSHR) coupled to G protein. TSHhyperactivation could be involved in thyroiddiseases and cancer. PKC,a serine/threonine protein kinase, has been widely implicated in malignanttransformation, cell survival, motility and invasion. Classical andnovel PKC are activated by PLC activation vía tyrosine kinases and G protein-coupledreceptors. Numerous studiesestablished that PKC is overexpressed in human cancer and its expressioncorrelates with tumor aggressiveness in prostate, lung and breast cancer. However,the role of PKC in thyroid cancer remains poorly studied. Wehere addressed the potentialrole of PKC in TSHR transduction pathways involved in cellular proliferationand tumorigenesis. Analysis of PKCexpression in human thyroid cancer cell lines (2 papilar, 1 follicular and 3 anaplastic)revealed high protein and mRNA levels relative to 2 ?normal? immortalized celllines. Treatment of thyroid cancer cells with TSHinduced an increase in cellular proliferation compared to untreated cells (Ct)(p<0.05 vs Ct) by cell titter blue assay (CTB). Treatment with pan-PKC inhibitors Staurosporine(St) and GF109203X (GF) resulted in a significant inhibition of TSH-mediatedproliferation compared to control in every cell line studied by CTB (p<0.05vs Ct). Also, treatment with St and GF diminished AKTand Erk activation in TSH-stimulated cells by western blot. Finally, PKCa-depleted cells by RNAireduced significantly TSH-induced proliferation by CTB and anchorage-dependentcolony formation. Our results show that PKCa is implicated in AKT and Erk phosphorylation bywestern blot. Our findingsestablish a potential role for PKC in the control of hormone-inducedproliferation that can be exploredas treatment to effectively eliminate thyroid cancer cells.