Publications by authors named "Lucio Cocco"

208 Publications

Foreword.

Authors:
Lucio Cocco

Adv Biol Regul 2021 01 13;79:100785. Epub 2021 Jan 13.

Bologna, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jbior.2021.100785DOI Listing
January 2021

Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia.

Int J Mol Sci 2021 Jan 15;22(2). Epub 2021 Jan 15.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy.

Erythropoiesis regulation is essential in normal physiology and pathology, particularly in myelodysplastic syndromes (MDS) and β-thalassemia. Several signaling transduction processes, including those regulated by inositides, are implicated in erythropoiesis, and the latest MDS or β-thalassemia preclinical and clinical studies are now based on their regulation. Among others, the main pathways involved are those regulated by transforming growth factor (TGF)-β, which negatively regulates erythrocyte differentiation and maturation, and erythropoietin (EPO), which acts on the early-stage erythropoiesis. Also small mother against decapentaplegic (SMAD) signaling molecules play a role in pathology, and activin receptor ligand traps are being investigated for future clinical applications. Even inositide-dependent signaling, which is important in the regulation of cell proliferation and differentiation, is specifically associated with erythropoiesis, with phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3K) as key players that are becoming increasingly important as new promising therapeutic targets. Additionally, Roxadustat, a new erythropoiesis stimulating agent targeting hypoxia inducible factor (HIF), is under clinical development. Here, we review the role and function of the above-mentioned signaling pathways, and we describe the state of the art and new perspectives of erythropoiesis regulation in MDS and β-thalassemia.
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http://dx.doi.org/10.3390/ijms22020827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830211PMC
January 2021

Sensitivity of pancreatic cancer cells to chemotherapeutic drugs, signal transduction inhibitors and nutraceuticals can be regulated by WT-TP53.

Adv Biol Regul 2021 01 7;79:100780. Epub 2021 Jan 7.

Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA, 27834. Electronic address:

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy. Approximately 85% of pancreatic cancers are classified as PDACs. The survival of PDAC patients is very poor and only 5-10% of patients survive 5 years after diagnosis. Mutations at the KRAS and TP53 gene are frequently observed in PDAC patients. The PANC-28 cell line lacks wild-type (WT) TP53. In the following study, we have investigated the effects of restoration of WT TP53 activity on the sensitivity of PANC-28 pancreatic cancer cells to various drugs which are used to treat PDAC patients as well as other cancer patients. In addition, we have examined the effects of signal transduction inhibitors which target critical pathways frequently deregulated in cancer. The effects of the anti-diabetes drug metformin and the anti-malarial drug chloroquine were also examined as these drugs may be repurposed to treat other diseases. Finally, the effects of certain nutraceuticals which are used to treat various ailments were also examined. Introduction of WT-TP53 activity in PANC-28 PDAC cells, can increase their sensitivity to various drugs. Attempts are being made clinically to increase TP53 activity in various cancer types which will often inhibit cell growth by multiple mechanisms.
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http://dx.doi.org/10.1016/j.jbior.2020.100780DOI Listing
January 2021

Location-dependent role of phospholipase C signaling in the brain: Physiology and pathology.

Adv Biol Regul 2021 01 28;79:100771. Epub 2020 Nov 28.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. Electronic address:

Phosphoinositide-specific phospholipases C (PI-PLCs) are a class of enzymes involved in the phosphatidylinositol metabolism, which is implicated in the activation of several signaling pathways and which controls several cellular processes. The scientific community has long accepted the existence of a nuclear phosphoinositide (PI) metabolism, independent from the cytoplasmic one, critical in nuclear function control. Indeed, nuclear PIs are involved in many activities, such as cell cycle regulation, cell proliferation, cell differentiation, membrane transport, gene expression and cytoskeletal dynamics. There are several types of PIs and enzymes implicated in brain activities and among these enzymes, PI-PLCs contribute to a specific and complex network in the developing nervous system. Moreover, considering the abundant presence of PI-PLCβ1, PI-PLCγ1 and PI-PLCβ4 in the brain, a specific role for each PLC subtype has been suggested in the control of neuronal activity, which is important for synapse function, development and other mechanisms. The focus of this review is to describe the latest research about the involvement of PI-PLC signaling in the nervous system, both physiologically and in pathological conditions. Indeed, PI-PLC signaling imbalance seems to be also linked to several brain disorders including epilepsy, movement and behavior disorders, neurodegenerative diseases and, in addition, some PI-PLC subtypes could become potential novel signature genes for high-grade gliomas.
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http://dx.doi.org/10.1016/j.jbior.2020.100771DOI Listing
January 2021

Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes.

Cell Mol Life Sci 2020 Oct 9. Epub 2020 Oct 9.

Cellular Signalling Laboratory, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.

Autosomal-dominant leukodystrophy (ADLD) is a rare fatal neurodegenerative disorder with overexpression of the nuclear lamina component, Lamin B1 due to LMNB1 gene duplication or deletions upstream of the gene. The molecular mechanisms responsible for driving the onset and development of this pathology are not clear yet. Vacuolar demyelination seems to be one of the most significant histopathological observations of ADLD. Considering the role of oligodendrocytes, astrocytes, and leukemia inhibitory factor (LIF)-activated signaling pathways in the myelination processes, this work aims to analyze the specific alterations in different cell populations from patients with LMNB1 duplications and engineered cellular models overexpressing Lamin B1 protein. Our results point out, for the first time, that astrocytes may be pivotal in the evolution of the disease. Indeed, cells from ADLD patients and astrocytes overexpressing LMNB1 show severe ultrastructural nuclear alterations, not present in oligodendrocytes overexpressing LMNB1. Moreover, the accumulation of Lamin B1 in astrocytes induces a reduction in LIF and in LIF-Receptor (LIF-R) levels with a consequential decrease in LIF secretion. Therefore, in both our cellular models, Jak/Stat3 and PI3K/Akt axes, downstream of LIF/LIF-R, are downregulated. Significantly, the administration of exogenous LIF can partially reverse the toxic effects induced by Lamin B1 accumulation with differences between astrocytes and oligodendrocytes, highlighting that LMNB1 overexpression drastically affects astrocytic function reducing their fundamental support to oligodendrocytes in the myelination process. In addition, inflammation has also been investigated, showing an increased activation in ADLD patients' cells.
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http://dx.doi.org/10.1007/s00018-020-03661-1DOI Listing
October 2020

Therapeutic resistance in breast cancer cells can result from deregulated EGFR signaling.

Adv Biol Regul 2020 12 28;78:100758. Epub 2020 Sep 28.

Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA. Electronic address:

The epidermal growth factor receptor (EGFR) interacts with various downstream molecules including phospholipase C (PLC)/protein kinase C (PKC), Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/GSK-3, Jak/STAT and others. Often these pathways are deregulated in human malignancies such as breast cancer. Various therapeutic approaches to inhibit the activity of EGFR family members including small molecule inhibitors and monoclonal antibodies (MoAb) have been developed. A common problem with cancer treatments is the development of drug-resistance. We examined the effects of a conditionally-activated EGFR (v-Erb-B:ER) on the resistance of breast cancer cells to commonly used chemotherapeutic drugs such as doxorubicin, daunorubicin, paclitaxel, cisplatin and 5-flurouracil as well as ionizing radiation (IR). v-Erb-B is similar to the EGFR-variant EGFRvIII, which is expressed in various cancers including breast, brain, prostate. Both v-Erb-B and EGFRvIII encode the EGFR kinase domain but lack key components present in the extracellular domain of EGFR which normally regulate its activity and ligand-dependence. The v-Erb-B oncogene was ligated to the hormone binding domain of the estrogen receptor (ER) which results in regulation of the activity of the v-Erb-ER construct by addition of either estrogen (E2) or 4-hydroxytamoxifen (4HT) to the culture media. Introduction of the v-Erb-B:ER construct into the MCF-7 breast cancer cell line increased the resistance to the cells to various chemotherapeutic drugs, hormonal-based therapeutics and IR. These results point to the important effects that aberrant expression of EGFR kinase domain can have on therapeutic resistance.
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http://dx.doi.org/10.1016/j.jbior.2020.100758DOI Listing
December 2020

Phospholipase C beta1 (PI-PLCbeta1)/Cyclin D3/protein kinase C (PKC) alpha signaling modulation during iron-induced oxidative stress in myelodysplastic syndromes (MDS).

FASEB J 2020 Nov 22;34(11):15400-15416. Epub 2020 Sep 22.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

MDS are characterized by anemia and transfusion requirements. Transfused patients frequently show iron overload that negatively affects hematopoiesis. Iron chelation therapy can be effective in these MDS cases, but the molecular consequences of this treatment need to be further investigated. That is why we studied the molecular features of iron effect and Deferasirox therapy on PI-PLCbeta1 inositide signaling, using hematopoietic cells and MDS samples. At baseline, MDS patients showing a positive response after iron chelation therapy displayed higher levels of PI-PLCbeta1/Cyclin D3/PKCalpha expression. During treatment, these responder patients, as well as hematopoietic cells treated with FeCl and Deferasirox, showed a specific reduction of PI-PLCbeta1/Cyclin D3/PKCalpha expression, indicating that this signaling pathway is targeted by Deferasirox. The treatment was also able to specifically decrease the production of ROS. This effect correlated with a reduction of IL-1A and IL-2, as well as Akt/mTOR phosphorylation. In contrast, cells exposed only to FeCl and cells from MDS patients refractory to Deferasirox showed a specific increase of ROS and PI-PLCbeta1/Cyclin D3/PKCalpha expression. All in all, our data show that PI-PLCbeta1 signaling is a target for iron-induced oxidative stress and suggest that baseline PI-PLCbeta1 quantification could predict iron chelation therapy response in MDS.
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http://dx.doi.org/10.1096/fj.202000933RRDOI Listing
November 2020

Cancer therapy and treatments during COVID-19 era.

Adv Biol Regul 2020 08 26;77:100739. Epub 2020 Jun 26.

Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27858, USA. Electronic address:

The COVID-19 pandemic has put a serious strain on health treatments as well at the economies of many nations. Unfortunately, there is not currently available vaccine for SARS-Cov-2/COVID-19. Various types of patients have delayed treatment or even routine check-ups and we are adapting to a virtual world. In many cases, surgeries are delayed unless they are essential. This is also true with regards to cancer treatments and screening. Interestingly, some existing drugs and nutraceuticals have been screened for their effects on COVID-19. Certain FDA approved drugs, vitamin, natural products and trace minerals may be repurposed to treat or improve the prevention of COVID-19 infections and disease progression. This review article will summarize how the treatments of various cancer patients has changed during the COVID-19 era as well as discuss the promise of some existing drugs and other agents to be repurposed to treat this disease.
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http://dx.doi.org/10.1016/j.jbior.2020.100739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319627PMC
August 2020

Subcellular Localization Relevance and Cancer-Associated Mechanisms of Diacylglycerol Kinases.

Int J Mol Sci 2020 Jul 26;21(15). Epub 2020 Jul 26.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.

An increasing number of reports suggests a significant involvement of the phosphoinositide (PI) cycle in cancer development and progression. Diacylglycerol kinases (DGKs) are very active in the PI cycle. They are a family of ten members that convert diacylglycerol (DAG) into phosphatidic acid (PA), two-second messengers with versatile cellular functions. Notably, some DGK isoforms, such as DGKα, have been reported to possess promising therapeutic potential in cancer therapy. However, further studies are needed in order to better comprehend their involvement in cancer. In this review, we highlight that DGKs are an essential component of the PI cycle that localize within several subcellular compartments, including the nucleus and plasma membrane, together with their PI substrates and that they are involved in mediating major cancer cell mechanisms such as growth and metastasis. DGKs control cancer cell survival, proliferation, and angiogenesis by regulating Akt/mTOR and MAPK/ERK pathways. In addition, some DGKs control cancer cell migration by regulating the activities of the Rho GTPases Rac1 and RhoA.
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http://dx.doi.org/10.3390/ijms21155297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432101PMC
July 2020

Influences of TP53 and the anti-aging DDR1 receptor in controlling Raf/MEK/ERK and PI3K/Akt expression and chemotherapeutic drug sensitivity in prostate cancer cell lines.

Aging (Albany NY) 2020 06 3;12(11):10194-10210. Epub 2020 Jun 3.

Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.

Background: TP53 plays critical roles in sensitivity to chemotherapy, and aging. Collagen is very important in aging. The molecular structure and biochemical properties of collagen changes during aging. The discoidin domain receptor (DDR1) is regulated in part by collagen. Elucidating the links between TP53 and DDR1 in chemosensitivity and aging could improve therapies against cancer and aging.

Results: Restoration of WT-TP53 activity resulted in increased sensitivity to chemotherapeutic drugs and elevated expression of key components of the Raf/MEK/ERK, PI3K/Akt and DDR1 pathways. DDR1 could modulate the levels of Raf/MEK/ERK and PI3K/Akt pathways as well as sensitize the cells to chemotherapeutic drugs. In contrast, suppression of WT TP53 with a dominant negative (DN) TP53 gene, suppressed DDR1 protein levels and increased their chemoresistance.

Conclusion: Restoration of WT TP53 activity or increased expression of the anti-aging DDR1 collagen receptor can result in enhanced sensitivity to chemotherapeutic drugs. Our innovative studies indicate the important links between WT TP53 and DDR1 which can modulate Raf/MEK/ERK and PI3K/Akt signaling as well as chemosensitivity and aging.

Methods: We investigated the roles of wild type (WT) and mutant TP53 on drug sensitivity of prostate cancer cells and the induction of Raf/MEK/ERK, PI3K/Akt and DDR1 expression and chemosensitivity.
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http://dx.doi.org/10.18632/aging.103377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346063PMC
June 2020

Targeting GSK3 and Associated Signaling Pathways Involved in Cancer.

Cells 2020 04 30;9(5). Epub 2020 Apr 30.

Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858 USA.

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/β-catenin signaling and β-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-κB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth.
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http://dx.doi.org/10.3390/cells9051110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290852PMC
April 2020

Phosphoinositide-Dependent Signaling in Cancer: A Focus on Phospholipase C Isozymes.

Int J Mol Sci 2020 Apr 8;21(7). Epub 2020 Apr 8.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.

Phosphoinositides (PI) form just a minor portion of the total phospholipid content in cells but are significantly involved in cancer development and progression. In several cancer types, phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P] and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P] play significant roles in regulating survival, proliferation, invasion, and growth of cancer cells. Phosphoinositide-specific phospholipase C (PLC) catalyze the generation of the essential second messengers diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (InsP) by hydrolyzing PtdIns(4,5)P. DAG and InsP regulate Protein Kinase C (PKC) activation and the release of calcium ions (Ca) into the cytosol, respectively. This event leads to the control of several important biological processes implicated in cancer. PLCs have been extensively studied in cancer but their regulatory roles in the oncogenic process are not fully understood. This review aims to provide up-to-date knowledge on the involvement of PLCs in cancer. We focus specifically on PLCβ, PLCγ, PLCδ, and PLCε isoforms due to the numerous evidence of their involvement in various cancer types.
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http://dx.doi.org/10.3390/ijms21072581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177890PMC
April 2020

Nuclear Inositides and Inositide-Dependent Signaling Pathways in Myelodysplastic Syndromes.

Cells 2020 03 12;9(3). Epub 2020 Mar 12.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, 40126 Bologna, Italy.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by peripheral blood cytopenia and abnormal myeloproliferation, as well as a variable risk of evolution into acute myeloid leukemia (AML). The nucleus is a highly organized organelle with several distinct domains where nuclear inositides localize to mediate essential cellular events. Nuclear inositides play a critical role in the modulation of erythropoiesis or myelopoiesis. Here, we briefly review the nuclear structure, the localization of inositides and their metabolic enzymes in subnuclear compartments, and the molecular aspects of nuclear inositides in MDS.
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http://dx.doi.org/10.3390/cells9030697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140618PMC
March 2020

Inositide-Dependent Nuclear Signalling in Health and Disease.

Handb Exp Pharmacol 2020 ;259:291-308

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Nuclear inositides have a specific subcellular distribution that is linked to specific functions; thus their regulation is fundamental both in health and disease. Emerging evidence shows that alterations in multiple inositide signalling pathways are involved in pathophysiology, not only in cancer but also in other diseases. Here, we give an overview of the main features of inositides in the cell, and we discuss their potential as new molecular therapeutic targets.
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http://dx.doi.org/10.1007/164_2019_321DOI Listing
August 2020

Editorial.

Authors:
Lucio Cocco

Adv Biol Regul 2020 01 10;75:100689. Epub 2019 Dec 10.

Bologna, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jbior.2019.100689DOI Listing
January 2020

Recent advances in MDS mutation landscape: Splicing and signalling.

Adv Biol Regul 2020 01 5;75:100673. Epub 2019 Nov 5.

Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Recurrent cytogenetic aberrations, genetic mutations and variable gene expression have been consistently recognized in solid cancers and in leukaemia, including in Myelodysplastic Syndromes (MDS). Besides conventional cytogenetics, the growing accessibility of new techniques has led to a deeper analysis of the molecular significance of genetic variations. Indeed, gene mutations affecting splicing genes, as well as genes implicated in essential signalling pathways, play a pivotal role in MDS physiology and pathophysiology, representing potential new molecular targets for innovative therapeutic strategies.
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http://dx.doi.org/10.1016/j.jbior.2019.100673DOI Listing
January 2020

Abilities of β-Estradiol to interact with chemotherapeutic drugs, signal transduction inhibitors and nutraceuticals and alter the proliferation of pancreatic cancer cells.

Adv Biol Regul 2020 01 18;75:100672. Epub 2019 Oct 18.

Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27858, USA. Electronic address:

Improving the effects of chemotherapy and reducing the side effects are important goals in cancer research. Various approaches have been examined to enhance the effectiveness of chemotherapy. For example, signal transduction inhibitors or hormonal based approaches have been included with chemo- or radio-therapy. MIA-PaCa-2 and BxPC-3 pancreatic ductal adenocarcinoma (PDAC) cells both express the estrogen receptor (ER). The effects of β-estradiol on the growth of PDAC cells has not been examined yet the ER is expressed in PDAC cells. We have examined the effects of combining β-estradiol with chemotherapeutic drugs, signal transcription inhibitors, natural products and nutraceuticals on PDAC. In most cases, inclusion of β-estradiol with chemotherapeutic drugs increased chemosensitivity. These results indicate some approaches involving β-estradiol which may be used to increase the effectiveness of chemotherapeutic and other drugs on the growth of PDAC.
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http://dx.doi.org/10.1016/j.jbior.2019.100672DOI Listing
January 2020

The function of PLCγ1 in developing mouse mDA system.

Adv Biol Regul 2020 01 19;75:100654. Epub 2019 Sep 19.

School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, 689-798, South Korea; Korea Brain Research Institute, Daegu, 41062, South Korea. Electronic address:

During neural development, growing neuronal cells consistently sense and communicate with their surroundings through the use of signaling molecules. In this process, spatiotemporally well-coordinated intracellular signaling is a prerequisite for proper neuronal network formation. Thus, intense interest has focused on investigating the signaling mechanisms in neuronal structure formation that link the activation of receptors to the control of cell shape and motility. Recent studies suggest that Phospholipase C gamma1 (PLCγ1), a signal transducer, plays key roles in nervous system development by mediating specific ligand-receptor systems. In this overview of the most recent advances in the field, we discuss the mechanisms by which extracellular stimuli trigger PLCγ1 signaling and, the role PLCγ1 in nervous system development.
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http://dx.doi.org/10.1016/j.jbior.2019.100654DOI Listing
January 2020

Phospholipase C-β1 potentiates glucose-stimulated insulin secretion.

FASEB J 2019 10 3;33(10):10668-10679. Epub 2019 Jul 3.

School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, South Korea.

PLC-β exerts biologic influences through GPCR. GPCRs are involved in regulating glucose-stimulated insulin secretion (GSIS). Previous studies have suggested that PLC-βs might play an important role in pancreatic β cells. However, because of a lack of the specific inhibitors of PLC-β isozymes and appropriate genetic models, the function of specific PLC-β isozymes in pancreatic β cells and their physiologic relevance in the regulation of insulin secretion have not been studied so far. The present study showed that PLC-β1 was crucial for β-cell function by generation of each PLC-β conditional knockout mouse. Mice lacking PLC-β1 in β cells exhibited a marked defect in GSIS, leading to glucose intolerance. In studies, the secreted insulin level and Ca response in ; pancreas/duodenum homeobox protein 1 ()-Cre recombinase-estrogen receptor T2 () islets was lower than those in the islets under the high-glucose condition. PLC-β1 led to potentiate insulin secretion stimulation of particular G-protein-coupled receptors. ; mice fed a high-fat diet developed more severe glucose intolerance because of a defect in insulin secretion. The present study identified PLC-β1 as an important molecule that regulates β cell insulin secretion and can be considered a candidate for therapeutic intervention in diabetes mellitus.-Hwang, H.-J., Yang, Y. R., Kim, H. Y., Choi, Y., Park, K.-S., Lee, H., Ma, J. S., Yamamoto, M., Kim, J., Chae, Y. C., Choi, J. H., Cocco, L., Berggren, P.-O., Jang, H.-J., Suh, P.-G. Phospholipase Cβ1 potentiates glucose-stimulated insulin secretion.
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http://dx.doi.org/10.1096/fj.201802732RRDOI Listing
October 2019

AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity.

FASEB J 2019 08 16;33(8):9044-9061. Epub 2019 May 16.

IRCSS Istituto Ortopedico Rizzoli (IOR), Bologna, Italy.

Murine thymoma viral oncogene homolog (AKT) kinases target both cytosolic and nuclear substrates for phosphorylation. Whereas the cytosolic substrates are known to be closely associated with the regulation of apoptosis and autophagy or metabolism and protein synthesis, the nuclear substrates are, for the most part, poorly understood. To better define the role of nuclear AKT, potential AKT substrates were isolated from the nuclear lysates of leukemic cell lines using a phosphorylated AKT substrate antibody and identified in tandem mass spectrometry. Among the proteins identified was adenosine deaminase acting on RNA (ADAR)1p110, the predominant nuclear isoform of the adenosine deaminase acting on double-stranded RNA. Coimmunoprecipitation studies and kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively, and overexpression of the phosphomimic mutants ADAR1p110 (T738D) and ADAR2 (T553D) resulted in a 50-100% reduction in editase activity. Thus, activation of AKT has a direct and major impact on RNA editing.-Bavelloni, A., Focaccia, E., Piazzi, M., Raffini, M., Cesarini, V., Tomaselli, S., Orsini, A., Ratti, S., Faenza, I., Cocco, L., Gallo, A., Blalock, W. L. AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity.
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http://dx.doi.org/10.1096/fj.201800490RRDOI Listing
August 2019

Phosphoinositide 3 Kinase Signaling in Human Stem Cells from Reprogramming to Differentiation: A Tale in Cytoplasmic and Nuclear Compartments.

Int J Mol Sci 2019 04 24;20(8). Epub 2019 Apr 24.

Department of Biomedical Sciences, University of Bologna, Via Irnerio, 48, 40126 Bologna, Italy.

Stem cells are undifferentiated cells that can give rise to several different cell types and can self-renew. Given their ability to differentiate into different lineages, stem cells retain huge therapeutic potential for regenerative medicine. Therefore, the understanding of the signaling pathways involved in stem cell pluripotency maintenance and differentiation has a paramount importance in order to understand these biological processes and to develop therapeutic strategies. In this review, we focus on phosphoinositide 3 kinase (PI3K) since its signaling pathway regulates many cellular processes, such as cell growth, proliferation, survival, and cellular transformation. Precisely, in human stem cells, the PI3K cascade is involved in different processes from pluripotency and induced pluripotent stem cell (iPSC) reprogramming to mesenchymal and oral mesenchymal differentiation, through different and interconnected mechanisms.
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http://dx.doi.org/10.3390/ijms20082026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514809PMC
April 2019

Effects of the MDM-2 inhibitor Nutlin-3a on PDAC cells containing and lacking WT-TP53 on sensitivity to chemotherapy, signal transduction inhibitors and nutraceuticals.

Adv Biol Regul 2019 05 15;72:22-40. Epub 2019 Mar 15.

Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA, 27834. Electronic address:

Mutations at the TP53 gene are readily detected (approximately 50-75%) in pancreatic ductal adenocarcinoma (PDAC) patients. TP53 was previously thought to be a difficult target as it is often mutated, deleted or inactivated on both chromosomes in certain cancers. In the following study, the effects of restoration of wild-type (WT) TP53 activity on the sensitivities of MIA-PaCa-2 pancreatic cancer cells to the MDM2 inhibitor nutlin-3a in combination with chemotherapy, targeted therapy, as well as, nutraceuticals were examined. Upon introduction of the WT-TP53 gene into MIA-PaCa-2 cells, which contain a TP53 gain of function (GOF) mutation, the sensitivity to the MDM2 inhibitor increased. However, effects of nutlin-3a were also observed in MIA-PaCa-2 cells lacking WT-TP53, as upon co-treatment with nutlin-3a, the sensitivity to certain inhibitors, chemotherapeutic drugs and nutraceuticals increased. Interestingly, co-treatment with nutlin-3a and certain chemotherapeutic drug such as irinotecan and oxaliplatin resulted in antagonistic effects in cells both lacking and containing WT-TP53 activity. These studies indicate the sensitizing abilities that WT-TP53 activity can have in PDAC cells which normally lack WT-TP53, as well as, the effects that the MDM2 inhibitor nutlin-3a can have in both cells containing and lacking WT-TP53 to various therapeutic agents.
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http://dx.doi.org/10.1016/j.jbior.2019.03.002DOI Listing
May 2019

Response of high-risk MDS to azacitidine and lenalidomide is impacted by baseline and acquired mutations in a cluster of three inositide-specific genes.

Leukemia 2019 09 20;33(9):2276-2290. Epub 2019 Feb 20.

Cellular Signalling Laboratory, Human Anatomy Section, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Specific myeloid-related and inositide-specific gene mutations can be linked to myelodysplastic syndromes (MDS) pathogenesis and therapy. Here, 44 higher-risk MDS patients were treated with azacitidine and lenalidomide and mutations analyses were performed at baseline and during the therapy. Results were then correlated to clinical outcome, overall survival (OS), leukemia-free-survival (LFS) and response to therapy. Collectively, 34/44 patients were considered evaluable for response, with an overall response rate of 76.25% (26/34 cases): 17 patients showed a durable response, 9 patients early lost response and 8 patients never responded. The most frequently mutated genes were ASXL1, TET2, RUNX1, and SRSF2. All patients early losing response, as well as cases never responding, acquired the same 3 point mutations during therapy, affecting respectively PIK3CD (D133E), AKT3 (D280G), and PLCG2 (Q548R) genes, that regulate cell proliferation and differentiation. Moreover, Kaplan-Meier analyses revealed that this mutated cluster was significantly associated with a shorter OS, LFS, and duration of response. All in all, a common mutated cluster affecting 3 inositide-specific genes is significantly associated with loss of response to azacitidine and lenalidomide therapy in higher risk MDS. Further studies are warranted to confirm these data and to further analyze the functional role of this 3-gene cluster.
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http://dx.doi.org/10.1038/s41375-019-0416-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733710PMC
September 2019

Clusterin enhances AKT2-mediated motility of normal and cancer prostate cells through a PTEN and PHLPP1 circuit.

J Cell Physiol 2019 07 22;234(7):11188-11199. Epub 2018 Nov 22.

Department of Biomedical, Metabolic, and Neural Sciences, Section of Morphology, Signal Transduction Unit, University of Modena and Reggio Emilia, Modena, Italy.

Clusterin (CLU) is a chaperone-like protein with multiple functions. sCLU is frequently upregulated in prostate tumor cells after chemo- or radiotherapy and after surgical or pharmacological castration. Moreover, CLU has been documented to modulate the cellular homolog of murine thymoma virus akt8 oncogene (AKT) activity. Here, we investigated how CLU overexpression influences phosphatidylinositol 3'-kinase (PI3K)/AKT signaling in human normal and cancer epithelial prostate cells. Human prostate cells stably transfected with CLU were broadly profiled by reverse phase protein array (RPPA), with particular emphasis on the PI3K/AKT pathway. The effect of CLU overexpression on normal and cancer cell motility was also tested. Our results clearly indicate that CLU overexpression enhances phosphorylation of AKT restricted to isoform 2. Mechanistically, this can be explained by the finding that the phosphatase PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1), known to dephosphorylate AKT2 at S474, is markedly downregulated by CLU, whereas miR-190, a negative regulator of PHLPP1, is upregulated. Moreover, we found that phosphatase and tensin homolog (PTEN) was heavily phosphorylated at the inhibitory site S380, contributing to the hyperactivation of AKT signaling. By keeping AKT2 phosphorylation high, CLU dramatically enhances the migratory behavior of prostate epithelial cell lines with different migratory and invasive phenotypes, namely prostate normal epithelial 1A (PNT1A) and prostatic carcinoma 3 (PC3) cells. Altogether, our results unravel for the first time a circuit by which CLU can switch a low migration phenotype toward a high migration phenotype, through miR-190-dependent downmodulation of PHLPP1 expression and, in turn, stabilization of AKT2 phosphorylation.
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http://dx.doi.org/10.1002/jcp.27768DOI Listing
July 2019

Therapeutic potential of nvp-bkm120 in human osteosarcomas cells.

J Cell Physiol 2019 07 7;234(7):10907-10917. Epub 2018 Dec 7.

Department of Biomedical Sciences, University of Bologna, Bologna, Italy.

Osteosarcoma (OS) is the most common pediatric malignant neoplasia of the skeletal system. It is characterized by a high degree of malignancy and a severe tendency to metastasize. In the past decade, many studies have provided evidence that the phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently altered pathways in human cancer, and has a critical role in driving tumor initiation and progression. Here, we have analyzed the therapeutic potential of the pan-PI3K inhibitor NVP-BKM120, which has recently entered clinical Phase II for treatment of PI3K-dependent cancers on three OS cell lines. We observed a concentration- and time-dependent decrease of Ser473 p-Akt as well as reduced levels of Thr37/46 p-4E-BP1, an indicator of the mammalian target of rapamycin complex 1 activity. All OS cell lines used in this study responded to BKM120 treatment with an arrest of cell proliferation, an increase in cell mortality, and an increase in caspase-3 activity. MG-63 cells were the most responsive cell line, demonstrating a significant increase in sub-G1 cells, and a rapid induction of cell death. Furthermore, we demonstrate that BKM120 is more effective when used in combination with other standard chemotherapeutic drugs. Combining BKM120 with vincristine demonstrated a more synergistic effect than BKM120 with doxorubicin in all the lines. Hence, we suggest that BKM120 may be a novel therapy for the treatment of OS presenting with anomalous upregulation of the PI3K signaling pathway.
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http://dx.doi.org/10.1002/jcp.27911DOI Listing
July 2019

Phospholipase C-β1 interacts with cyclin E in adipose- derived stem cells osteogenic differentiation.

Adv Biol Regul 2019 01 5;71:1-9. Epub 2018 Nov 5.

Section of Human Anatomy, Department of Biomedical and Neuromotor Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy. Electronic address:

Adipose-derived stem cells (ADSCs) are multipotent mesenchymal stem cells that have the ability to differentiate into several cell types, including chondrocytes, osteoblasts, adipocytes, and neural cells. Given their easy accessibility and abundance, they became an attractive source of mesenchymal stem cells, as well as candidates for developing new treatments for reconstructive medicine and tissue engineering. Our study identifies a new signaling pathway that promotes ADSCs osteogenic differentiation and links the lipid signaling enzyme phospholipase C (PLC)-β1 to the expression of the cell cycle protein cyclin E. During osteogenic differentiation, PLC-β1 expression varies concomitantly with cyclin E expression and the two proteins interact. These findings contribute to clarify the pathways involved in osteogenic differentiation and provide evidence to develop therapeutic strategies for bone regeneration.
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http://dx.doi.org/10.1016/j.jbior.2018.11.001DOI Listing
January 2019

Endoscopic endonasal approach to primitive Meckel's cave tumors: a clinical series.

Acta Neurochir (Wien) 2018 12 31;160(12):2349-2361. Epub 2018 Oct 31.

Department of Neurosurgery, DIBINEM, University of Bologna, Bologna, Italy.

Introduction: Recently, an alternative endoscopic endonasal approach to Meckel's cave (MC) tumors has been proposed. To date, few studies have evaluated the results of this route. The aim of our study was to evaluate long-term surgical and clinical outcome associated with this technique in a cohort of patients with intrinsic MC tumors.

Methods: All patients with MC tumors treated at out institution by endoscopic endonasal approach (EEA) between 2002 and 2016 were included. Patients underwent brain MRI, CT angiography, and neurological evaluation before surgery. Complications were considered based on the surgical records. All examinations were repeated after 3 and 12 months, then annually. The median follow-up was of 44.1 months (range 16-210).

Results: The series included 8 patients (4 F): 5 neuromas, 1 meningioma, 1 chondrosarcoma, and 1 epidermoid cyst. The median age at treatment was 54.5 years (range 21-70). Three tumors presented with a posterior fossa extension. Radical removal of the MC portion of the tumor was achieved in 7 out of 8 cases. Two patients developed a permanent and transitory deficit of the sixth cranial nerve, respectively. No tumor recurrence was observed at follow-up.

Conclusion: In this preliminary series, the EEA appeared an effective and safe approach to MC tumors. The technique could be advantageous to treat tumors located in the antero-medial aspects of MC displacing the trigeminal structures posteriorly and laterally. A favorable index of an adequate working space for this approach is represented by the ICA medialization, while tumor extension to the posterior fossa represents the main limitation to radical removal of this route.
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http://dx.doi.org/10.1007/s00701-018-3708-4DOI Listing
December 2018

Abilities of berberine and chemically modified berberines to inhibit proliferation of pancreatic cancer cells.

Adv Biol Regul 2019 01 17;71:172-182. Epub 2018 Oct 17.

Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27858, USA. Electronic address:

Berberine (BBR) is a common nutraceutical consumed by millions worldwide. BBR has many different effects on human health, e.g., diabetes, diarrhea, inflammation and now more recently it has been proposed to have potent anti-cancer effects. BBR has been shown to suppress the growth of cancer cells more than normal cells. BBR has been proposed to exert its growth-inhibitory effects by many different biochemical mechanisms including: suppression of cell cycle progression, induction of reactive oxygen species, induction of apoptosis and autophagy and interactions with DNA potentially leading to DNA damage, and altered gene expression. Pancreatic cancer is a leading cancer worldwide associated with a poor prognosis. As our population ages, pancreatic cancer has an increasing incidence and will likely become the second leading cause of death from cancer. There are few truly-effective therapeutic options for pancreatic cancer. Surgery and certain chemotherapeutic drugs are used to treat pancreatic cancer patients. Novel approaches to treat pancreatic cancer patients are direly needed as they usually survive for less than a year after being diagnosed. In the following manuscript, we discuss the abilities of BBR and certain chemically-modified BBRs (NAX compounds) to suppress growth of pancreatic cancer cells.
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http://dx.doi.org/10.1016/j.jbior.2018.10.003DOI Listing
January 2019

The regulation of insulin secretion via phosphoinositide-specific phospholipase Cβ signaling.

Adv Biol Regul 2019 01 23;71:10-18. Epub 2018 Sep 23.

School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea. Electronic address:

Phospholipase Cβ (PLCβ) is a membrane-associated enzyme activated by membrane receptors, especially G-protein coupled receptors (GPCRs). It propagates intracellular signaling by mediating phospholipid metabolism and generating key second messengers, such as inositol triphosphate and diacylglycerol, leading to intracellular Ca mobilization and activation of kinases, such as protein kinases C. In pancreatic β-cells, PLCβ-mediated signaling activated by various factors, such as free fatty acids and neuronal and hormonal ligands, has been confirmed as being involved in the regulation of insulin secretion, and PLCβs have been regarded as essential mediators for augmenting insulin secretion. In this review, we describe the physiological function of PLCβs in the regulation of glucose-stimulated insulin secretion and discuss emerging data on GPCR/PLCβ signaling that is being developed as a target for the treatment of diabetes mellitus.
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http://dx.doi.org/10.1016/j.jbior.2018.09.011DOI Listing
January 2019