THYROID HORMONE MEMBRANE RECEPTOR INHIBITION IN THE TREATMENT WITH REXINOIDS OF CUTANEOUS T CELL LYMPHOMA

DEBERNARDI M; PAULAZO A; STERLE H; DIAZ FLAQUÉ MC; CERCHIETTI L; CREMASCHI GA; CAYROL F

Congreso; Reunion Conjunta de Sociedades de Biociencias 2017; 2017

CTCL are exposed to a complex paracrine and endocrine environment that influence their progression from skin to visceral disease. One of the most common treatments for CTCL, the rexinoid bexarotene (Bex), is associated with hypothyroidism being patients candidate for thyroid hormone (TH) replacement therapy. We recently found that TH, mostly through the action on its membrane receptor (mTR, integrin aVb3) is required for the proliferation of T cell lymphomas (TCL), including CTCL. The consequences of TH administration on the activity of Bex in CTCL cells are unknown. Our aim was to study the effect of TH on the anti-lymphoma activity of rexinoids.We first evaluate cell viability and apoptosis induction of human CTCL cells HuT78 and MJ and murine TCL EL4 cells treated with Bex in the presence and absence of physiological levels of TH. As expected, Bex decreased the viability and induce apoptosis on all the cell lines, but in presence of TH both effects decreased by 15-40% (p<0.01). These results support the notion that Bex should not be administered with TH replacement. However, beside the metabolic dysfunction, hypothyroidism could also favor tumor progression.We thus determine if the inhibition of the mTR would be sufficient to decrease the pro-survival effect of TH on cells treated with Bex. We found that the inhibitor of the integrin aVb3, cilengitide, not only avoided the pro-survival effect of TH but increased the activity of Bex in vitro on HuT78, MJ and EL4 cells. We also found that the combination of both drugs results in a significant increase in the inhibition of the transcriptional expression of anti apoptotic (BCL2, BCL2L1) and cell cycle genes (Cyclins) and in the induction of proapoptotic genes (BID, BAX) (in all the cases at least p<0.05 vs Bex alone).These results will be the rationale to perform in vivo experiments using a murine model of EL4 LCT tumor to evaluate if this mechanism can be therapeutically capitalized to improve Bex treatment.