APO866, an inhibitor of
NAD biosynthesis, exhibits potent antitumor properties in various
malignancies. Recently, it has been shown that
APO866 induces apoptosis and autophagy in human hematological
cancer cells, but the role of autophagy in APO866-induced cell death remains unclear. Here, we report studies on the molecular mechanisms underlying APO866-induced cell death with emphasis on autophagy. Treatment of
leukemia and
lymphoma cells with
APO866 induced both autophagy, as evidenced by an increase in autophagosome formation and in SQSTM1/p62 degradation, but also increased
caspase activation as revealed by
CASP3/
caspase 3 cleavage. As an underlying mechanism, APO866-mediated autophagy was found to deplete CAT/
catalase, a reactive oxygen species (ROS) scavenger, thus promoting ROS production and cell death. Inhibition of autophagy by ATG5 or ATG7 silencing prevented CAT degradation, ROS production,
caspase activation, and APO866-induced cell death. Finally, supplementation with exogenous CAT also abolished
APO866 cytotoxic activity. Altogether, our results indicated that autophagy is essential for
APO866 cytotoxic activity on cells from
hematological malignancies and also indicate an autophagy-dependent CAT degradation, a novel mechanism for APO866-mediated cell killing. Autophagy-modulating approaches could be a new way to enhance the antitumor activity of
APO866 and related agents.