Selective inhibition of cell death in malignant vs normal B-cell precursors: implications for cAMP in development and treatment of BCP-ALL

Naderi, Elin Hallan; Ugland, Hege Grefslie; Diep, Phoi-Phoi; Josefsen, Dag; Naderi, Soheil; Blomhoff, Heidi Kiil

doi:10.1182/blood-2012-08-452698

Cited by 12 publications

(27 citation statements)

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“…In line with this hypothesis, increased intracellular cAMP levels and PKA activity following morphine treatment lead to inhibition of Rac1GTPase and p38 MAPK, cause attenuation of actin polymerization, and decrease bacterial phagocytosis (51). cAMP plays an important and sometimes controversial role in apoptosis (52,53), but cAMP is also a well-established inhibitor of cell migration (20) and a regulator of cytoskeleton organization (54). It was demonstrated that cAMP inhibits the Rho family small GTPases via PKA.…”

Section: Discussionmentioning

confidence: 91%

Inhibition of the GTPase Rac1 Mediates the Antimigratory Effects of Metformin in Prostate Cancer Cells

Dirat

Ader

Golzio

et al. 2015

Molecular Cancer Therapeutics

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Cell migration is a critical step in the progression of prostate cancer to the metastatic state, the lethal form of the disease. The antidiabetic drug metformin has been shown to display antitumoral properties in prostate cancer cell and animal models; however, its role in the formation of metastases remains poorly documented. Here, we show that metformin reduces the formation of metastases to fewer solid organs in an orthotopic metastatic prostate cancer cell model established in nude mice. As predicted, metformin hampers cell motility in PC3 and DU145 prostate cancer cells and triggers a radical reorganization of the cell cytoskeleton. The small GTPase Rac1 is a master regulator of cytoskeleton organization and cell migration. We report that metformin leads to a major inhibition of Rac1 GTPase activity by interfering with some of its multiple upstream signaling pathways, namely P-Rex1 (a Guanine nucleotide exchange factor and activator of Rac1), cAMP, and CXCL12/CXCR4, resulting in decreased migration of prostate cancer cells. Importantly, overexpression of a constitutively active form of Rac1, or P-Rex, as well as the inhibition of the adenylate cyclase, was able to reverse the antimigratory effects of metformin. These results establish a novel mechanism of action for metformin and highlight its potential antimetastatic properties in prostate cancer. Mol Cancer Ther; 14(2); 586-96. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 91%

Inhibition of the GTPase Rac1 Mediates the Antimigratory Effects of Metformin in Prostate Cancer Cells

Dirat

Ader

Golzio

et al. 2015

Molecular Cancer Therapeutics

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“…Indeed, PGE2 has been shown to be toxic to B-ALL cells (59,60). Because PGE2 also protects B-ALL from DNA damage-induced cell death (61,62), it might be most effective by enhancing dex cytotoxicity in a twodrug combination.…”

Section: Discussionmentioning

confidence: 99%

Relapse-associated AURKB blunts the glucocorticoid sensitivity of B cell acute lymphoblastic leukemia

Poulard

Kim

Fang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoids (GCs) are used in combination chemotherapies as front-line treatment for B cell acute lymphoblastic leukemia (B-ALL). Although effective, many patients relapse and become resistant to chemotherapy and GCs in particular. Why these patients relapse is not clear. We took a comprehensive, functional genomics approach to identify sources of GC resistance. A genome-wide shRNA screen identified the transcriptional coactivators EHMT2, EHMT1, and CBX3 as important contributors to GC-induced cell death. This complex selectively supports GC-induced expression of genes contributing to cell death. A metaanalysis of gene expression data from B-ALL patient specimens revealed that Aurora kinase B (AURKB), which restrains GC signaling by phosphorylating EHMT1-2, is overexpressed in relapsed B-ALL, suggesting it as a potential contributor to relapse. Inhibition of AURKB enhanced GC-induced expression of cell death genes, resulting in potentiation of GC cytotoxicity in cell lines and relapsed B-ALL patient samples. This function for AURKB is distinct from its canonical role in the cell cycle. These results show the utility of functional genomics in understanding mechanisms of resistance and rapidly identifying combination chemotherapeutics.

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“…Paediatric BCP-ALLs generally retain wild type p53 [ 8 ], and are thus forced to suppress p53 activity through indirect measures. We have previously demonstrated that elevated levels of cyclic adenosine monophosphate (cAMP) can suppress DNA damage-induced p53 accumulation by promoting the interaction between p53 and its negative regulator HDM2, thereby attenuating the resulting cell death in BCP-ALL blasts [ 9 - 11 ]. cAMP is an important physiological signal transducer in lymphocytes [ 12 - 14 ], and it is generated by adenylate cyclase (AC) upon ligand binding to a subgroup of G protein-coupled receptors (GPCRs) activating the stimulatory alpha subunit G αs .…”

Section: Introductionmentioning

confidence: 99%

“…This, together with our observation that cAMP attenuates the expression of p53 led us to postulate that elevated cAMP levels might function as a tumour promoting mechanism in development of BCP-ALL. The basal levels of intracellular cAMP in isolated BCP-ALLs are comparable to those of normal BCPs [ 11 ], and we therefore considered the possibility that BCP-ALLs could produce high levels of cAMP in response to certain physiological extracellular signals.…”

Section: Introductionmentioning

confidence: 99%

“…The role of tumour stroma-derived PGE 2 has been extensively studied in solid tumours [ 26 ], however, little is known about its potential role in leukaemia physiology. Having recently shown that PGE 2 can suppress the p53 levels and cell death when added to cell cultures of BCP-ALL cells [ 11 ], we have now explored the possible role of BM stroma-derived PGE 2 on BCP-ALL p53 levels and cell survival. In agreement with our hypothesis, our results suggest that bone marrow microenvironment (BMME)-secreted PGE 2 , through its inhibitory effects on p53 accumulation and cell death, could contribute to the protective effect of the BMME towards BCP-ALL cells.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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.

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Selective inhibition of cell death in malignant vs normal B-cell precursors: implications for cAMP in development and treatment of BCP-ALL

Cited by 12 publications

References 50 publications

Inhibition of the GTPase Rac1 Mediates the Antimigratory Effects of Metformin in Prostate Cancer Cells

Inhibition of the GTPase Rac1 Mediates the Antimigratory Effects of Metformin in Prostate Cancer Cells

Relapse-associated AURKB blunts the glucocorticoid sensitivity of B cell acute lymphoblastic leukemia

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

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