cAMP-mediated autophagy inhibits DNA damage-induced death of leukemia cells independent of p53.

cAMP-mediated autophagy inhibits DNA damage-induced death of leukemia cells independent of p53. Oncotarget. 2018 Jul 13;9(54):30434-30449 Authors: Skah S, Richartz N, Duthil E, Gilljam KM, Bindesbøll C, Naderi EH, Eriksen AB, Ruud E, Dirdal MM, Simonsen A, Blomhoff HK Abstract 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 ...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research