Activation of cAMP signaling inhibits DNA damage-induced apoptosis in BCP-ALL cells through abrogation of p53 accumulation.
In lymphocytes, the second messenger cyclic adenosine monophosphate (cAMP) plays a well-established antiproliferative role through inhibition of G(1)/S transition and S-phase progression. We have previously demonstrated that, during S-phase arrest, cAMP inhibits the action of S phase-specific cytotoxic compounds, leading to reduction in their apoptotic response. In this report, we provide evidence that cAMP can also inhibit the action of DNA-damaging agents independently of its effect on S phase. Elevation of cAMP in B-cell precursor acute lymphoblastic leukemia cells is shown to profoundly inhibit the apoptotic response to ionizing radiation, anthracyclins, alkylating agents, and platinum compounds. We further demonstrate that this effect depends on the ability of elevated cAMP levels to quench DNA damage-induced p53 accumulation by increasing the p53 turnover, resulting in attenuated Puma and Bax induction, mitochondrial outer membrane depolarization, caspase activation, and poly(ADP-ribose) polymerase cleavage. On the basis of our findings, we suggest that cAMP levels may influence p53 function in malignant cells that retain wild-type p53, potentially affecting p53 both as a tumor suppressor during cancer initiation and maintenance, and as an effector of the apoptotic response to DNA-damaging agents during anticancer treatment.
Naderi
Elin Hallan
EH
Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo/Universitetet i Oslo, Blindern, Oslo, Norway.
Findley
Harry W
HW
Ruud
Ellen
E
Blomhoff
Heidi Kiil
HK
Naderi
Soheil
S
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D011839:Radiation, Ionizing; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D016159:Tumor Suppressor Protein p53; D000242:Cyclic AMP