THYROID HORMONES (THS) ACTING THROUGH INTEGRIN ΑVΒ3 INDUCE ONCOGENIC SIGNALING PATHWAYS INVOLVED IN T CELL LYMPHOMA (TCL) PROGRESSION

DEBERNARDI MM; DIAZ ALBUJA, JA; STERLE HA; PAULAZO MA; DIAZ FLAQUÉ MC; CAMPOS HAEDO MN; GONZALEZ G; ROSEMBLIT C; CREMASCHI GA; CAYROL F

Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2022; 2022

Decoding the molecular mechanisms leading to TCL progressionis a complex issue due to the diversity of these malignancies. Inmost TCL patients the JAK/STAT and NF-κB pathways are over-ac-tivated. To find new therapeutic targets, these oncogenic pathways,and the activating factors should be studied deeply. Our previousresults show that THs, acting via integrin αVβ3, promotes cell pro-liferation and survival, and induces an angiogenic program in TCLcells. Here we study if THs are one of the factors involved in theactivation of these oncogenic pathways. First, we analyzed TCL celllines corresponding to immature (CUTLL1) and mature (OCI-Ly12,OCI-Ly13.2) human subtypes after 10, 15, and 30 minutes THstreatment. We found that physiological levels of THs significantlyincrease STAT1, 3, 5, NF-κB, and ERK phosphorylation in all TCLcells (p<0.05). As GATA3 overexpression is associated with a poorprognosis in TCL patients, we also analyzed it and found that, after48 hours, THs significantly increase GATA3 protein levels (p<0.05).Similar results were found in EL-4 murine TCL cells (p<0.05). Inter-estingly, THs effects on STATs phosphorylation and GATA3 expres-sion were blunted by the integrin αVβ3 inhibitor, cilengitide (p<0.05).Moreover, we found that cilengitide was able to decrease in vivoSTAT1 and 5 phosphorylation (p<0.01) in EL4 tumors growing invivo in a syngeneic murine model. Finally, we study how THs actionsaffect the sphingomyelinases (SMases) pathway. We found that theinhibitors of the neutral (imipramine), or acidic (GW4869) SMasessignificantly revert TH effects on cell proliferation (p<0.05), highlight-ing the importance of this signaling pathway in TCL cells.Our results provide the rational basis to continue studying the mo-lecular mechanisms of THs actions in malignant cells; this couldlead to the identification of new therapeutic targets, like integrinαVβ3, to improve current treatments for TCL patients.