Bone marrow stroma-derived PGE2 protects BCP-ALL cells from DNA damage-induced p53 accumulation and cell death

Abstract

BackgroundB cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common paediatric cancer. BCP-ALL blasts typically retain wild type p53, and are therefore assumed to rely on indirect measures to suppress transformation-induced p53 activity. We have recently demonstrated that the second messenger cyclic adenosine monophosphate (cAMP) through activation of protein kinase A (PKA) has the ability to inhibit DNA damage-induced p53 accumulation and thereby promote survival of the leukaemic blasts.Development of BCP-ALL in the bone marrow (BM) is supported by resident BM-derived mesenchymal stromal cells (MSCs). MSCs are known to produce prostaglandin E2 (PGE2) which upon binding to its receptors is able to elicit a cAMP response in target cells. We hypothesized that PGE2 produced by stromal cells in the BM microenvironment could stimulate cAMP production and PKA activation in BCP-ALL cells, thereby suppressing p53 accumulation and promoting survival of the malignant cells.MethodsPrimary BCP-ALL cells isolated from BM aspirates at diagnosis were cocultivated with BM-derived MSCs, and effects on DNA damage-induced p53 accumulation and cell death were monitored by SDS-PAGE/immunoblotting and flow cytometry-based methods, respectively. Effects of intervention of signalling along the PGE2-cAMP-PKA axis were assessed by inhibition of PGE2 production or PKA activity. Statistical significance was tested by Wilcoxon signed-rank test or paired samples t test.ResultsWe demonstrate that BM-derived MSCs produce PGE2 and protect primary BCP-ALL cells from p53 accumulation and apoptotic cell death. The MSC-mediated protection of DNA damage-mediated cell death is reversible upon inhibition of PGE2 synthesis or PKA activity. Furthermore our results indicate differences in the sensitivity to variations in p53 levels between common cytogenetic subgroups of BCP-ALL.ConclusionsOur findings support our hypothesis that BM-derived PGE2, through activation of cAMP-PKA signalling in BCP-ALL blasts, can inhibit the tumour suppressive activity of wild type p53, thereby promoting leukaemogenesis and protecting against therapy-induced leukaemic cell death. These novel findings identify the PGE2-cAMP-PKA signalling pathway as a possible target for pharmacological intervention with potential relevance for treatment of BCP-ALL.

Effects of human amnion–derived mesenchymal stromal cell transplantation in rats with radiation proctitis

“…It has been reported that bone marrow-derived MSCs produce PGE 2 and protect primary B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells from p53 accumulation and apoptosis [40]. Our group has also recently demonstrated that AMSCs produce large amounts of PGE 2 as compared with chorion-derived MSCs, and AMSC-CM is rich in HGF, bFGF, IGF-1, and VEGF [26].…”

Interaction of MSC with tumor cells

“…In this context, MSC-derived prostaglandin E2 contributed to protect lymphoblastic leukemia cells from DNA-damage induced p53 accumulation and cell death via PKA supporting a tumor promoting role of MSC in the TME [45, 46]. …”

miR-146a is Upregulated During Retinal Pigment Epithelium (RPE)/Choroid Aging in Mice and Represses IL-6 and VEGF-A Expression in RPE Cells

“…In a recent study, miR-146a has been shown to downregulate VEGF expression in cancer cells (29). To examine the function of miR-146 in RPE cells, miR-146a or control mimic was transfected into ARPE-19 cells; cells without transfection were also used as an additional control.…”

“…It has been recently shown to inhibit cancer metastasis by downregulating VEGF expression in cancer cells (29). Our results that miR-146a mimic represses VEGF-A expression and TNF-α induced IL-6 expression in ARPE-19 cells is consistent with the previous results using other cell types.…”