86 research outputs found
Role of inositide signalling regulation in higher-risk MDS patients during epigenetic therapy
No full textBackground: Inositide signalling pathways are involved in cell
growth, differentiation and apoptosis and play a role in
the progression of myelodysplastic syndromes (MDS) towards
acute myeloid leukemia (AML). The combination of the DNA
methyltransferase inhibitor azacitidine (AZA) and the HDAC inhibitor
valproic acid (VPA) in patients with IPSS intermediate-2/high-risk
MDS has been demonstrated to be active and associated with a high
response rate in patients with MDS and unfavourable prognosis
(Voso MT et al, 2009).
Introduction: In the last few years, our group demonstrated not
only that phosphoinositide-phospholipase C beta1 (PI-PLCbeta1)
promoter gene is hyper-methylated in higher-risk MDS, but also that is affected by epigenetic therapy (Follo MY et al, PNAS 2009; Follo
MY et al. Leukemia 2010). Indeed, AZA, alone or in combination with
VPA was able to induce PI-PLCbeta1 demethylation and expression.
Purpose: In this study we further investigated the role of lipid
signalling pathways during epigenetic therapy, focusing on the
functional effect of AZA and VPA on PI-PLCbeta1 promoter in highrisk
MDS patients.
Materials and Methods: The study included 20 higher-risk MDS
patients (IPSS risk: intermediate-2 or high): 8 of them were treated
with AZA alone (75 mg/m2/day SC for 7 days/28 days), whereas 6 of
them received the combination of AZA with VPA (600–1500 mg/daily
orally) and the remaining 6 were treated only with best supportive
care. For each patient we analyzed the effect of epigenetic therapy
in correlation to PI-PLCbeta1 signalling, by analyzing the binding
affinity of transcription factors correlated to hematopoietic stem
cell differentiation and proliferation, as well as by quantifyng the
expression of molecules involved in the epigenetic machinery, such
as Class I HDACs.
Results: 8/20 (40%) of our MDS patients showed a favourable
hematologic response to epigenetic therapy and an increase in PIPLCbeta1
expression, as compared with the pre-treatment period,
thus confirming the involvement of this molecule in response
to demethylating agents. Moreover, MDS patients responding to
epigenetic treatment seem to involve the recruitment of specific
transcription factors on PI-PLCbeta1 promoter during the regulation
of methylation processes. Taken together, our data are consistent
with the hypothesis of a correlation between epigenetic treatment
and PI-PLCbeta1 signalling, thus hinting at a role for PI-PLCbeta1 in
monitoring the efficacy of epigenetic therapy and paving the way
for the development of innovative therapeutic strategies in MD
Effect of azacitidine on inositide-dependent signalling pathways in low-risk MDS patients
No full textBackground: Azacitidine is a DNA methyltransferase inhibitor
currently used for the treatment of higher-risk myelodysplastic
syndromes (MDS) which has also been proven an effective treatment
of lower-risk MDS (Silverman LR et al, J Clin Oncol 2002; Musto P
et al, Cancer 2010). Inositide signalling is involved in cell growth,
differentiation and apoptosis, therefore affecting cell processes and
playing a role in the pathogenesis of several malignancies.
Introduction: Our group recently demonstrated that phosphoinositide-phospholipase
C beta1 (PI-PLCbeta1) is involved in the
MDS progression to AML and is affected by epigenetic therapy
(Follo MY et al, J Cell Biochem 2010; Follo MY et al, Leukemia
2010). Namely, PI-PLCbeta1 specifically targets Cyclin D3, which
is in turn implicated in hematopoietic stem cell proliferation and
differentiation.
Purpose: In this study, we analyzed the role of PI-PLCbeta1-
dependent signalling pathways during epigenetic therapy, focusing
on the effect of azacitidine on PI-PLCbeta1 downstream target Cyclin
D3 in lower-risk MDS patients.
Materials and Methods: The analysis included 25 patients (IPSS risk:
low or intermediate-1) treated with azacitidine alone (75 mg/m2
subcutaneous daily for 5 consecutive days every 28 days, for a total
of 8 courses). For each patient we followed the effect of azacitidine
in correlation to both PI-PLCbeta1 and Cyclin D3 expression.
Results: Our results show that 9/25 (36%) of our lower-risk MDS
patients showed a hematologic response to azacitidine (Complete
Remission: 4 patients, Partial Remission: 1 patient, Hematologic
Improvements: 4 patients), as well as an increase in PI-PLCbeta1
expression, as compared with pre-treatment levels. Furthermore,
ongoing analyses are trying to disclose whether Cyclin D3 activation
is also implicated in azacitidine response, therefore affecting
hematopoietic stem cell differentiation processes.
Conclusions: Overall, our data hint at a correlation between
azacitidine therapy and PI-PLCbeta1 signalling, possibly via the
activation of Cyclin D3, even in lower-risk MDS, thus indicating
that PI-PLCbeta1 could be useful not only for evaluating the efficacy
of azacitidine but also for disclosing the molecular mechanisms
underlying this kind of treatment in lower-risk MD
Glycogen Synthase Kinase-3 and phospholipase C-beta signalling: Roles and possible interactions in myelodysplastic syndromes and acute myeloid leukemia
No full textGSK-3 and PLCbeta enzymes are responsible for the regulation of several signalling pathways related to many cellular functions. In hematopoietic cells, GSK-3 deficiency is correlated with an MDS-like phenotype and with leukemogenesis, showing a prognostic potential in AML cells. GSK-3 interacts with Wnt or MAPK signalling, but it is also linked to PI3K/Akt/mTOR pathways to regulate cell proliferation and apoptosis of hematopoietic stem cell progenitors. PLCbeta enzymes are involved in cell cycle progression of hematopoietic, MDS/AML and immune cells, through activation of PKC or calcium signalling. Of note, a PLCbeta1/PKCalpha pathway is modulated during MDS pathogenesis, with a specific involvement of the inositides localized in the nucleus. Here we focus on GSK-3 and PLCbeta signalling, describing the many evidences that underline the pivotal role of both GSK-3 and PLCbeta-dependent pathways in MDS/AML, their association with therapy and their possible interactions
Nuclear phosphoinositide specific phospholipase C (PI-PLC)-ss1: a central intermediary in nuclear lipid-dependent signal transduction
No full textSeveral studies have demonstrated the existence of an autonomous intranuclear phosphoinositide cycle that involves the activation of nuclear PI-PLC and the generation of diacylglycerol (DG) within the nucleus. Although several distinct isozymes of PI-PLC have been detected in the nucleus, the isoform that has been most consistently highlighted as being nuclear is PI-PLC-beta 1. Nuclear PI-PLC-beta 1 has been linked with either cell proliferation or differentiation. Remarkably, the activation mechanism of nuclear PI-PLC-beta 1 has been shown to be different from its plasma membrane counterpart, being dependent on phosphorylation effected by p44/42 mitogen activated protein (MAP) kinase. In this review, we report the most up-dated findings about nuclear PI-PLC-beta 1, such as the localization in nuclear speckles, the activity changes during the cell cycle phases, and the possible involvement in the progression of myelodisplastic syndrome to acute myeloid leukemia
Nuclear PI-PLCbeta1-Lamin B1 complex signalling during cell cycle progression in human erytholeukemia cells
No full text
Effect of PKC inhibition on low and fast proliferating Morris rat hepatoma cell line progression
No full textNuclear phospholipase C signaling through type 1 IGF receptor and its involvement in cell growth and differentiation
No full textThe existence of a nuclear polyphosphoinositol metabolism, independent from that at the plasma cell membrane, is now widely recognized. Specific changes in the nuclear phosphatidylinositol (PtdIns) metabolism have been implicated in cell growth, differentiation and neoplastic transformation. Here, the main features of nuclear inositol lipid signaling through type I IGF receptor, is reviewed with particular attention to the role of inositide-specific phospholipase C (PI-PLC) beta 1 in cell proliferation and differentiation, due to the peculiar localization of this molecule in the nuclear compartment
PI-PLCβ1 gene copy number alterations in breast cancer
No full textDeregulation of signal transduction pathways frequently confers selective biological advantages to tumors. Phosphoinositides play an essential role in numerous cellular functions and, among the enzymes implicated in these processes, phosphoinositide-specific phospholipase C β1 (PI-PLCβ1) is one of the key regulators. In the present study, a fluorescence in situ hybridization (FISH) approach was used to investigate PI-PLCβ1 gene copy number alterations in various types of breast cancer differing in their invasiveness and proliferative activity, according to their mitotic index. At the molecular level, we also performed both real-time PCR and immunohistochemical analyses on PI-PLCβ1 to further investigate its expression in primary breast cancers. Finally, we analyzed the correlation between PI-PLCβ1 gene copy number and clinicopathological parameters. Our results show that most of our cases had aneusomies on the PI-PLCβ1 locus (20p12) and amplification of this specific region was the most frequent alteration observed. Our findings also indicate that the amplification of the region containing the PI-PLCβ1 gene was mostly related to the mitotic index, rather than to the invasion status. Finally, even though our case series is limited, PI-PLCβ1 gene amplification seems to be correlated to clinicopathological parameters
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