cAMP-Mediated Autophagy Promotes Cell Survival via ROS-Induced Activation of PARP1: Implications for Treatment of Acute Lymphoblastic Leukemia

• Published in: Molecular cancer research 2022-03, Vol.20 (3), p.400-411
• Main Authors: Richartz, Nina, Pietka, Wojciech, Gilljam, Karin M, Skah, Seham, Skålhegg, Bjørn S, Bhagwat, Sampada, Naderi, Elin Hallan, Ruud, Ellen, Blomhoff, Heidi Kiil
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Cell Survival; Child; Humans; Mice; Mice, Inbred NOD; NAD; Poly (ADP-Ribose) Polymerase-1 - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Reactive Oxygen Species
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-21-0652

DNA-damaging therapy is the basis for treatment of most cancers, including B-cell precursor acute lymphoblastic leukemia (BCP-ALL, hereafter ALL). We have previously shown that cAMP-activating factors present in the bone marrow render ALL cells less sensitive to DNA damage-induced apoptosis, by enhancing autophagy and suppressing p53. To sensitize ALL cells to DNA-damaging therapy, we have searched for novel targets that may counteract the effects induced by cAMP signaling. In the current study, we have identified PARP1 as a potential target. We show that the PARP1 inhibitors olaparib or PJ34 inhibit cAMP-mediated autophagy and thereby potentiate the DNA-damaging treatment. Furthermore, we reveal that cAMP-mediated PARP1 activation is preceded by induction of reactive oxygen species (ROS) and results in depletion of nicotinamide adenine dinucleotide (NAD), both of which are autophagy-promoting events. Accordingly, we demonstrate that scavenging ROS by N-acetylcysteine and repleting NAD independently reduce DNA damage-induced autophagy. In addition, olaparib augmented the effect of DNA-damaging treatment in a human xenograft model of ALL in NOD-scidIL2Rgammanull mice. On the basis of the current findings, we suggest that PARP1 inhibitors may enhance the efficiency of conventional genotoxic therapies and thereby provide a novel treatment strategy for pediatric patients with ALL. PARP1 inhibitors augment the DNA damage-induced killing of ALL cells by limiting the opposing effects of cAMP-mediated autophagy, which involves ROS-induced PARP1 activation and depletion of cellular NAD levels.