Ricerc@Sapienza

Aberrant Notch signaling is involved in the development of several diseases, including T-cell acute lymphoblastic leukemia (T-ALL). A better knowledge of T-ALL biology has led to the development of targeted therapies for the treatment of this disease. Recently, it has been reported the role of the unfolded protein response (UPR) in acute leukemias. UPR is an evolutionary conserved pathway which restores protein homeostasis after Endoplasmatic Reticulum (ER) stress. Juglone, a naturally-occurring naphtoquinone, is considered a promising anticancer agent for its strong activity against cancer cells in in vitro and in vivo models, including leukemia. Preliminary results showed the mechanism whereby Juglone induces apoptosis in T-ALL. Time course studies indicated that initial apoptotic events are driven by the inhibition of proteasome activity, which contributes to the induction of endoplasmic reticulum (ER) stress. Moreover, Juglone treatment induced Notch signaling down-regulation. Notably, Notch3 (N3) inhibition (but not Notch1) was able to amplify Juglone-induced T-ALL cell apoptosis through UPR perturbation, thus finally leading to a defective cell response to the prolonged Juglone-induced ER stress. Given the obtained results, our main aims will be to widen our research evaluating how N3 is involved in sustaining UPR signaling in vitro and performing xenograft experiments to evaluate the anti-tumor effects of Juglone in vivo.