Activation of cAMP signaling inhibits DNA damage–induced apoptosis in BCP-ALL cells through abrogation of p53 accumulation

Abstract

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 DNAdamaging agents during anticancer treatment. (Blood. 2009;114:608-618) IntroductionThe p53 tumor suppressor is a sequence-specific transcription factor located at the nexus of a complex signaling network, on which signals of various types of cellular stress converge. In humans, the importance of p53 as a tumor suppressor is highlighted by the high frequency of somatic mutations encountered in sporadic cancers, 1 as well as by the high incidence and early onset of tumors observed in Li-Fraumeni patients carrying germline mutations of TP53. 2 In tumors retaining wild-type p53, its function is thought to be suppressed by viral proteins, deregulation of components of the p53 regulatory circuit, or disruption of upstream or downstream signaling pathways. 3 Under normal conditions, p53 is expressed at low levels in the cell because of its rapid degradation. In response to activating signals such as DNA damage, p53 is stabilized and accumulates in the nucleus, where it activates transcription of p53-responsive target genes, leading to phenotypic alterations, including cell-cycle arrest, senescence, or apoptosis. The outcome of p53 activation depends on cell type and the nature and context of DNA damage. For instance, hematopoietic cells typically undergo apoptosis in response to DNA damage, an event that requires the induction of the p53-target gene Puma. [4][5][6] Although activation of p53 constitutes a major barrier to cancer initiation and progression, it is also thought to play an important role in induction of cell death in response to anticancer treatments such as radiation therapy and various chemotherapeutic agents. Indeed, abolition of the p53 function in cancer tissue has been shown to contribute to therapy resistance. 7 Cycli...

cAMP signalling inhibits p53 acetylation and apoptosis via HDAC and SIRT deacetylases

“…2). In accordance with previous findings (16,24), exposure of cells to IR in the presence of TSA or NIA increased the IR-mediated acetylation of p53. However, pretreatment of cells with both TSA and NIA substantially further enhanced the p53 acetylation induced by IR.…”

“…Elevation of intracellular cAMP levels has an inhibitory effect on DNA damage-induced apoptosis in normal lymphoid cells as well as BCP-ALL cells (16). We have previously shown that this inhibitory effect of cAMP is mediated through its ability to abrogate the DNA damage-induced p53-HDM2 dissociation, leading to restoration of p53 degradation in DNA-damaged cells (17).…”

“…Our lab has previously reported that elevation of cAMP in lymphoid cells leads to arrest in the G1 phase of the cell cycle (12)(13)(14), arrest in the S phase and inhibition of apoptosis by anticancer agents (15). Using B cell precursor acute lymphoblastic leukaemia (BCP-ALL) cells as a model system, we also reported that the inhibitory effect of cAMP on apoptosis is p53-dependent (16), and that cAMP antagonizes the disruption of p53-HDM2 interaction by DNA damage (17). It was therefore of interest to further investigate the mechanism by which cAMP abolishes IR-induced p53 stability and apoptosis in these cells, and in particular, reveal how cAMP signaling promotes the interaction between p53 and HDM2.…”

Integrated analysis using methylation and gene expression microarrays reveals PDE4C as a prognostic biomarker in human glioma

“…Furthermore, previous studies have shown that activation of cAMP signaling inhibits DNA damage-induced apoptosis in BCP-ALL cells through abrogation of p53 accumulation and promotion of p53 and HDM2 interaction (8,16). However, PDE4C remains a putative tumor suppressor, as it has not been identified in gliomas.…”

“…Previous studies have shown that the expression of genes related to glioma progression include COL4A2, FOXM1, MGP, TOP2A, CENPF, IGFBP4, VEGFA, ADD3, CAMK2G, KI-67, YKL-40 and SMAD4, all of which are associated with the World Health Organization (WHO) glioma grade (4-6). Moreover, gene methylation is believed to play a crucial role in tumor progression, partially by repressing tumor suppressor genes, inhibiting their accumulation and inducing their mutation (7,8). Conversely, prognostic markers with potential clinical significance have been identified through genome-…”