cAMP-mediated autophagy inhibits DNA damage-induced death of leukemia cells independent of p53
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Seham Skah1,*, Nina Richartz1,*, Eva Duthil1, Karin M. Gilljam1, Christian Bindesbøll1, Elin Hallan Naderi2, Agnete B. Eriksen1, Ellen Ruud3,4, Marta M. Dirdal3, Anne Simonsen1,5 and Heidi Kiil Blomhoff1
1Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
2Department of Oncology, Section for Head and Neck Oncology, Oslo University Hospital, Oslo, Norway
3Department of Hematology and Oncology, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
4Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
5Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
*These authors have contributed equally to this work
Heidi Kiil Blomhoff, email: firstname.lastname@example.org
Keywords: cAMP-signaling; autophagy; DNA damage; p53; apoptosis
Received: March 14, 2018 Accepted: June 23, 2018 Published: July 13, 2018
Autophagy is important in regulating the balance between cell death and survival, with the tumor suppressor p53 as one of the key components in this interplay. We have previously utilized an in vitro model of the most common form of childhood cancer, B cell precursor acute lymphoblastic leukemia (BCP-ALL), to show that activation of the cAMP signaling pathway inhibits p53-mediated apoptosis in response to DNA damage in both cell lines and primary leukemic cells. The present study reveals that cAMP-mediated survival of BCP-ALL cells exposed to DNA damaging agents, involves a critical and p53-independent enhancement of autophagy. Although autophagy generally is regarded as a survival mechanism, DNA damage-induced apoptosis has been linked both to enhanced and reduced levels of autophagy. Here we show that exposure of BCP-ALL cells to irradiation or cytotoxic drugs triggers autophagy and cell death in a p53-dependent manner. Stimulation of the cAMP signaling pathway further augments autophagy and inhibits the DNA damage-induced cell death concomitant with reduced nuclear levels of p53. Knocking-down the levels of p53 reduced the irradiation-induced autophagy and cell death, but had no effect on the cAMP-mediated autophagy. Moreover, prevention of autophagy by bafilomycin A1 or by the ULK-inhibitor MRT68921, diminished the protecting effect of cAMP signaling on DNA damage-induced cell death. Having previously proposed a role of the cAMP signaling pathway in development and treatment of BCP-ALLs, we here suggest that inhibitors of autophagy may improve current DNA damage-based therapy of BCP-ALL - independent of p53.
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