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.
There is a need to improve T-ALL therapy, especially for relapsing patients as their prognosis is dismal and treatment options are very limited1.
Since the link between the UPR and cancers has been amply established as the UPR is highly activated in a number of cancers2, it is becoming increasingly clear that the UPR can be therapeutically exploited to reduce the survivability of cells that rapidly proliferate and possess developed secretory capabilities, such as leukemia cells, or tip the balance towards apoptosis. Indeed, the intensity and duration of endoplasmic reticulum (ER) stress converts the unfolded protein response from an adaptive into a terminal response. The first regulates homeostasis, the latter triggers apoptosis3.
Activation of terminal UPR by either blockade of adaptive UPR or exaggeration of ER stress has been explored as a novel approach in cancer therapy2. Here, we will take advantage of the Juglone ability of acting in both ways since preliminary results showed that Juglone induces apoptosis in Notch3-overexpressing cell lines increasing ER stress and perturbing UPR. Moreover, Juglone-induced UPR alteration was significantly amplified by Notch3-downregulation, thus suggesting a possible role of Notch3 in sustaining UPR.
These findings may have important therapeutic implications for the subset of Notch3-overexpressing T-ALLs, considering the emerging interest in generating new anticancer multi-target agents for their ability to interfere simultaneously with multiple altered pathways, thus finally suggesting a more selective novel strategy that could reduce side-effects of the current treatments.
References
1 Ksionda et al., 2018; 2 Park et al., 2013; 3 Randal et al., 2017.