Targeting oncogenic Notch signaling with SERCA inhibitors
Luca Pagliaro, Matteo Marchesini, Giovanni Roti
Abstract
Abstract P-type ATPase inhibitors are among the most successful and widely prescribed therapeutics in modern pharmacology. Clinical transition has been safely achieved for H + /K + ATPase inhibitors such as omeprazole and Na + /K + -ATPase inhibitors like digoxin. However, this is more challenging for Ca 2+ -ATPase modulators due to the physiological role of Ca 2+ in cardiac dynamics. Over the past two decades, sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA) modulators have been studied as potential chemotherapy agents because of their Ca 2+ -mediated pan-cancer lethal effects. Instead, recent evidence suggests that SERCA inhibition suppresses oncogenic Notch1 signaling emerging as an alternative to γ-secretase modulators that showed limited clinical activity due to severe side effects. In this review, we focus on how SERCA inhibitors alter Notch1 signaling and show that Notch on-target-mediated antileukemia properties of these molecules can be achieved without causing overt Ca 2+ cellular overload.