Publications (29)100.54 Total impact
-
Article: Prostate cancer cells metabolize D-lactate inside mitochondria via a D-lactate dehydrogenase which is more active and highly expressed than in normal cells.
[show abstract] [hide abstract]
ABSTRACT: Although D-lactate metabolism has been shown to occur in a variety of mitochondria, the metabolic fate of D-lactate in cancer cells has never been investigated, as it is believed to be exported to the extracellular phase. We show that mitochondria from both cancer (PC-3) and normal (PNT1A) prostate cells can metabolize D-lactate in an energy competent manner. This is due to the mitochondrial D-lactate dehydrogenase, a membrane flavoprotein, the activity and protein level of which are higher in PC-3 than in PNT1A cells, as detected by both kinetic and immunological analysis. D-lactate can enter prostate mitochondria and cause the export of newly synthesized malate in a carrier-mediated manner, with the rate of malate efflux from mitochondria twofold higher in cancer.FEBS letters 01/2013; · 3.54 Impact Factor -
Article: Stress-related mitochondrial components and mitochondrial genome as targets of anticancer therapy.
[show abstract] [hide abstract]
ABSTRACT: In addition to their role as cell powerhouse mitochondria are key organelles in the processes deciding about cell life or death that are crucial for tumor cell growth and survival, as well as for tumor cell ability to metastasize. Alterations in mitochondrial structure and functions have long been observed in cancer cells, thus targeting mitochondria as an anticancer therapeutic strategy has gained momentum recently. We will review the achievements and perspectives in the elucidation of the molecular basis for developing mitochondrial-targeted compounds as potential anticancer agents with special attention to mitochondrial DNA mutations and mitochondrial dysfunction. Molecules/agents candidate to affect mitochondrial metabolism in cancer cells will be dealt with, with a particular focus on approaches targeting defects in the mitochondrial genome.Chemical Biology & Drug Design 01/2013; 81(1):102-12. · 2.28 Impact Factor -
Article: Skp2 overexpression is associated with loss of BRCA2 protein in human prostate cancer.
[show abstract] [hide abstract]
ABSTRACT: BRCA2 (breast cancer 2, early onset) is a tumor suppressor gene that confers increased susceptibility for prostate cancer (PCa). Previous in vitro experiments demonstrated that Skp2, an E3 ubiquitin ligase aberrantly overexpressed in PCa, is involved in the proteolytic degradation of BRCA2 in PCa cells, suggesting that the BRCA2-Skp2 interaction may play a role in prostate tumorigenesis. Herein, we investigated BRCA2 and Skp2 expression during PCa development using a prostate TMA. Although luminal and basal benign prostate epithelium exhibited moderate to strong nuclear BRCA2 immunostaining, the intensity and number of positive nuclei decreased significantly in high-grade prostatic intraepithelial neoplasia and PCa. Decreased frequency and intensity of nuclear BRCA2 labeling were inversely correlated with Skp2 expression in high-grade prostatic intraepithelial neoplasia and PCa. To functionally assess the effects of BRCA2 and Skp2 expression on prostate malignant transformation, we overexpressed Skp2 in normal immortalized prostate cells. Skp2 overexpression reduced BRCA2 protein and promoted cell growth and migration. A similar phenotype was observed after reduction of BRCA2 protein levels using specific BRCA2 small-interfering RNA. Forced BRCA2 expression in Skp2-overexpressing stable transfectants inhibited the migratory and growth properties by >60%. These results show that loss of BRCA2 expression during prostate tumor development is strongly correlated with both migratory behavior and cancer growth and include Skp2 as a BRCA2 proteolytic partner in vivo.American Journal Of Pathology 05/2011; 178(5):2367-76. · 4.89 Impact Factor -
Article: Aromatase deficiency inhibits the permeability transition in mouse liver mitochondria.
[show abstract] [hide abstract]
ABSTRACT: Lack of estrogens affects male physiology in a number of ways, including severe changes in liver metabolism that result in lipid accumulation and massive hepatic steatosis. Here we investigated whether estrogen deficiency may alter the functionality and permeability properties of liver mitochondria using, as an experimental model, aromatase knockout (ArKO) male mice, which cannot synthesize endogenous estrogens due to a disruption of the Cyp19 gene. Liver mitochondria isolated from ArKO mice displayed increased activity of the mitochondrial respiratory complex IV compared with wild-type mice and were less prone to undergo cyclosporin A-sensitive mitochondrial permeability transition (MPT) induced by calcium loading. The altered permeability properties of the mitochondrial membranes were not due to changes in reactive oxygen species, ATP levels, or mitochondrial membrane potential but were associated with increased content of the phospholipid cardiolipin, structural component of the mitochondrial membranes and regulator of the MPT pore, and with increased mitochondrial protein levels of Bcl-2 and the adenine nucleotide translocator (ANT), regulator and component of the MPT pore, respectively. Real-time RT-PCR demonstrated increased mRNA levels for Bcl-2 and ANT2 but not for the ANT1 isoform in ArKO livers. Supplementation of 17beta-estradiol retrieved ArKO mice from massive hepatic steatosis and restored mitochondrial permeability properties, cardiolipin, Bcl-2, and ANT2 levels. Overall, our findings demonstrate an important role of estrogens in the modulation of hepatic mitochondrial function and permeability properties in males and suggest that estrogen deficiency may represent a novel positive regulator of Bcl-2 and ANT2 proteins, two inhibitors of MPT occurrence and powerful antiapoptotic molecules.Endocrinology 03/2010; 151(4):1643-52. · 4.46 Impact Factor -
Article: Changes in ultrastructure and the occurrence of permeability transition in mitochondria during rat liver regeneration
[show abstract] [hide abstract]
ABSTRACT: Mitochondrial bioenergetic impairment has been found in the organelles isolated from rat liver during the prereplicative phase of liver regeneration. To gain insight into the mechanism underlying this impairment, we investigated mitochondrial ultrastructure and membrane permeability properties in the course of liver regeneration after partial hepatectomy, with special interest to the role played by Ca2+ in this process. The results show that during the first day after partial hepatectomy, significant changes in the ultrastructure of mitochondria in situ occur. Mitochondrial swelling and release from mitochondria of both glutamate dehydrogenase and aspartate aminotransferase isoenzymes with an increase in the mitochondrial Ca2+ content were also observed. Cyclosporin-A proved to be able to prevent the changes in mitochondrial membrane permeability properties. At 24 h after partial hepatectomy, despite alteration in mitochondrial membrane permeability properties, no release of cytochrome c was found. The ultrastructure of mitochondria, the membrane permeability properties and the Ca2+ content returned to normal values during the replicative phase of liver regeneration. These results suggest that, during the prereplicative phase of liver regeneration, the changes in mitochondrial ultrastructure observed in liver specimens were correlated with Ca2+-induced permeability transition in mitochondria.European Journal of Biochemistry. 08/2009; 269(13):3304 - 3312. -
Article: Beta1 integrin cytoplasmic variants differentially regulate expression of the antiangiogenic extracellular matrix protein thrombospondin 1.
[show abstract] [hide abstract]
ABSTRACT: Beta(1) integrins play an important role in regulating cell proliferation and survival. Using small interfering RNA or an inhibitory antibody to beta(1), we show here that, in vivo, beta(1) integrins are essential for prostate cancer growth. Among the five known beta(1) integrin cytoplasmic variants, two have been shown to differentially affect prostate cell functions. The beta(1A) variant promotes normal and cancer cell proliferation, whereas the beta(1C) variant, which is down-regulated in prostate cancer, inhibits tumor growth and appears to have a dominant effect on beta(1A). To investigate the mechanism by which beta(1C) inhibits the tumorigenic potential of beta(1A), we analyzed changes in gene expression in cells transfected with either beta(1C) or beta(1A). The results show that beta(1C) expression increases the levels of an extracellular matrix protein, thrombospondin 1 (TSP1), an angiogenesis inhibitor. TSP1 protein levels are increased upon beta(1C) expression in prostate cancer cells as well as in beta(1)-null GD25 cells. We show that TSP1 does not affect proliferation, apoptosis, or anchorage-independent growth of prostate cancer cells. In contrast, the newly synthesized TSP1, secreted by prostate cancer cells expressing beta(1C), prevents proliferation of endothelial cells. In conclusion, our novel findings indicate that expression of the beta(1C) integrin variant in prostate glands prevents cancer progression by up-regulation of TSP1 levels and inhibition of angiogenesis.Cancer Research 07/2009; 69(13):5374-82. · 7.86 Impact Factor -
Article: Loss of BRCA2 promotes prostate cancer cell invasion through up-regulation of matrix metalloproteinase-9.
[show abstract] [hide abstract]
ABSTRACT: BRCA2 is a multifunctional tumor suppressor protein which plays critical roles in DNA repair, transcription, and cell proliferation, and the loss of which has been linked to the biology of several types of cancers. Here, on prostate adenocarcinoma specimens from 80 patients, we demonstrate that BRCA2 protein is lost in carcinoma cells compared to normal and hyperplastic prostate epithelium. Using highly metastatic prostate cancer PC-3 cells, we show that while BRCA2 depletion by small-interfering RNA promoted migration onto the extracellular matrix proteins fibronectin, laminin, and collagens, as well as invasion through the reconstituted basement membrane matrix Matrigel by more than 140%, recombinant BRCA2 overexpression decreased both phenomena by 57-80% and changed cell morphology from angular and spindle to round and compact. The BRCA2 inhibitory effect on cancer cell migration and invasion resulted from down-regulation of matrix metalloproteinase (MMP)-9 protein levels due to increased MMP-9 proteolysis, and was signaled through inhibition of PI3-kinase/AKT and activation of MAPK/ERK pathway. In BRCA2-overexpressing PC-3 cells, transient transfection with a constitutively active PI3-kinase mutant or treatment with the MAPK/ERK inhibitor PD98059 rescued MMP-9 levels and restored the migratory and invasive capabilities. Consistently, PI3-kinase inhibition with a dominant-negative mutant or MAPK/ERK activation with a gain-of-function mutant reduced MMP-9 levels and prevented migration and invasion in wild-type PC-3 cells. These results provide novel evidence showing that a functional BRCA2 protein may limit the metastatic potential of neoplastic cells by down-regulating MMP-9 production through inhibition of PI3-kinase/AKT and activation of MAPK/ERK, effectively hindering cancer cell migration and invasion.Cancer Science 04/2008; 99(3):553-63. · 3.33 Impact Factor -
Article: Mitochondrial DNA depletion reduces PARP-1 levels and promotes progression of the neoplastic phenotype in prostate carcinoma.
[show abstract] [hide abstract]
ABSTRACT: Mitochondrial dysfunction resulting from mitochondrial DNA (mtDNA) mutations and/or depletion has been correlated with cancer progression and drug resistance. To investigate the role of mtDNA in prostate cancer progression, we used LNCaP and PC-3 prostate carcinoma cells as experimental model. Compared to minimally invasive androgen-dependent LNCaP cells, highly invasive androgen-independent PC-3 cells, as well as androgen-independent DU145 and C4-2 cells, exhibited significantly reduced mtDNA content. In PC-3 cells, reduction of mtDNA was accompanied by decreased mitochondrial membrane potential (DeltaPsi(m)), increased migration onto the basement membrane protein laminin-1, reduced chemosensitivity to paclitaxel (IC(50)=110 nM vs. 22 nM) and decreased expression of poly(ADP-ribose) polymerase (PARP)-1. To investigate the relationship between mtDNA depletion and these phenotypic characteristics, we established mtDNA-depleted LNCaP cells [Rho(-)] by long-term exposure to ethidium bromide or treated wild-type LNCaP cells with a mitochondrial ionophore, carbonyl cyanide m-chlorophenylhydrazone. Both manipulations resulted in DeltaPsi(m) loss, acquisition of invasive cytology, increased motility onto laminin-1, reduced sensitivity to paclitaxel (IC(50)= approximately 100 nM) and approximately 75% reduction in PARP-1 protein levels, resembling PC-3 cells. Overall, these results provide novel evidence demonstrating that mtDNA depletion in early prostate carcinoma may contribute to the acquisition of a more invasive phenotype that is less sensitive to paclitaxel-induced apoptosis.Cellular oncology: the official journal of the International Society for Cellular Oncology 02/2008; 30(4):307-22. · 4.17 Impact Factor -
Article: Nitric oxide has dual opposite roles during early and late phases of apoptosis in cerebellar granule neurons.
[show abstract] [hide abstract]
ABSTRACT: The involvement and the role of nitric oxide (NO) as a signaling molecule in the course of neuronal apoptosis, whether unique or modulated during the progression of the apoptotic program, has been investigated in a cellular system consisting of cerebellar granule cells (CGCs) where apoptosis can be induced by lowering extracellular potassium. Several parameters involved in NO signaling pathway, such as NO production, neuronal nitric oxide synthase (nNOS) expression, and cyclic GMP (cGMP) production were examined in the presence or absence of different inhibitors. We provide evidence that nitric oxide has dual and opposite effects depending on time after induction of apoptosis. In an early phase, up to 3 h of apoptosis, nitric oxide supports survival of CGCs through a cGMP-dependent mechanism. After 3 h, nNOS expression and activity decreased resulting in shut down of NO and cGMP production. Residual NO then contributes to the apoptotic process by reacting with rising superoxide anions leading to peroxynitrite production and protein inactivation. We conclude that whilst NO over-production protects neurons from death in the early phase of neuronal damage, its subsequent reduction may contribute to neuronal degeneration and ultimate cell death.APOPTOSIS 10/2007; 12(9):1597-610. · 4.79 Impact Factor -
Article: Constitutive activation of MAPK/ERK inhibits prostate cancer cell proliferation through upregulation of BRCA2.
[show abstract] [hide abstract]
ABSTRACT: BRCA2 is central to an utterly diverse biological behavior elicited after integrin-mediated normal and prostate cancer cell adhesion to basement membrane (BM) and extracellular matrix (ECM) proteins. Unlike normal cells, adhesive stimuli in cancer cells activate PI 3-kinase/AKT signaling resulting in BRCA2 degradation and unchecked cancer cell proliferation and metastasis. However, the precise mechanisms involved in normal BRCA2 homeostasis are unknown. We investigated ERK and AKT phosphorylation in normal (PNT1A) and cancer (PC-3) prostate cells after adhesion to ECM and the effects upon BRCA2 and cell proliferation. PNT1A cell adhesion to ECM triggered MAPK/ERK signaling resulting in upregulation of BRCA2 mRNA and protein, with negligible effects upon cell proliferation. Disruption of MAPK/ERK with PD98059 prevented any BRCA2 upregulation inhibiting DNA synthesis below basal levels. PC-3 cells exhibited a defective MAPK/ERK pathway that was unresponsive to adhesion to the ECM, which instead triggered PI 3-kinase/AKT signaling leading to BRCA2 protein depletion and cell proliferation. Reconstitution of MAPK/ERK by recombinant expression of a constitutively active form of MAPK kinase 1 (MEK1) effectively reversed the neoplastic phenotype by increasing BRCA2 expression and preventing any aberrant cell proliferation at rest and upon interaction with ECM proteins. Our results suggest that aberrant loss of MAPK/ERK activity in prostate cancer may play a pivotal role in the malignant phenotype, and provide evidence that interventions aimed at bypassing the signaling block are able to effectively reverse neoplastic unchecked cell proliferation.International Journal of Oncology 02/2007; 30(1):217-24. · 2.40 Impact Factor -
Article: Up-regulation of Skp2 after prostate cancer cell adhesion to basement membranes results in BRCA2 degradation and cell proliferation.
[show abstract] [hide abstract]
ABSTRACT: Aberrant interaction of carcinoma cells with basement membranes (BM) is a fundamental pathophysiological process that initiates a series of events resulting in cancer cell invasion and metastasis. In this report, we describe the results of our investigations pertaining to the events triggered by the adhesion of normal (PNT1A) and highly metastatic (PC-3) prostate cells onto BM proteins. Unlike PNT1A, PC-3 cells adhered avidly to Matrigel BM matrix as well as to isolated collagen type IV, laminin, and heparan sulfate proteoglycan perlecan, main BM components. This aberrantly increased cancer cell adhesion resulted in sustained BRCA2 protein depletion and vigorous cell proliferation, a cascade triggered by beta1 integrin-mediated phosphatidylinositol 3-kinase activation leading to BRCA2 degradation in the proteasome. This latter effect was orchestrated by phosphatidylinositol 3-kinase-dependent up-regulation of Skp2, a subunit of the Skp1-Cul1-F-box protein ubiquitin complex that directly associates with BRCA2 as demonstrated by coimmunoprecipitation assays, determines its ubiquitination, and ultimately targets it for proteasomal degradation. Inhibition of Skp2 expression by small interference RNA prevented BRCA2 depletion and inhibited the trophic effect upon cell proliferation. These results provide additional evidence on the role of BRCA2 as a modulator of cancer cell growth and elucidate the molecular mechanisms involved in its down-regulation in cancer cells when interacting with BM, a crucial step in the biology of metastasis. Furthering the understanding of this molecular pathway may prove valuable in designing new therapeutic strategies aimed at modifying the natural history of prostate carcinoma.Journal of Biological Chemistry 09/2006; 281(31):22100-7. · 4.77 Impact Factor -
Article: Hepatocyte 'priming' and increase in transforming growth factor-beta1 mRNA expression are delayed in hypothyroid versus euthyroid rats during liver regeneration.
[show abstract] [hide abstract]
ABSTRACT: Hypothyroidism decreases liver weight and delays the compensatory liver growth after partial hepatectomy (PH) as compared with the euthyroid condition. The aim of this study was to investigate, in hypothyroid rats, the mRNA expression of genes modulating these effects, focusing on c-fos and c-myc, hallmarks of hepatocyte 'priming', and on transforming growth factor-beta1 (TGF-beta1) and its receptor, the transforming growth factor-beta1 receptor-type II (TbetaR-II), negative regulators of liver growth. Euthyroid and hypothyroid male Wistar rats underwent 70% PH and total RNA was isolated from frozen liver samples removed at basal state and during regeneration, 0-144 h after surgery. In this study, we show for the first time that, in the basal liver state, hypothyroidism increased TGF-beta1 and TbetaR-II mRNA levels by 45% and 30%, respectively, as compared with the euthyroid condition and, after PH, resulted in a approximately 12-h delay in the activation of c-fos and c-myc mRNA expression. Moreover, the increase in TGF-beta1 mRNA levels, detected 24-48 h after PH in euthyroid rats, was delayed by 72 h in hypothyroid rats, occurring when a concomitant reduction in TbetaR-II was measured. These results suggest that, in hypothyroid rats, at the basal liver level, the increase in mRNA expression of genes that negatively regulate liver growth might be involved in the decrease in liver weight and that, after PH, the delay of hepatocyte 'priming' and coordinated changes in mRNA expression of negative regulators of liver regeneration might be involved in delaying the regenerative process.International Journal of Molecular Medicine 07/2006; 17(6):1063-8. · 1.98 Impact Factor -
Article: Beta1 integrins modulate cell adhesion by regulating insulin-like growth factor-II levels in the microenvironment.
[show abstract] [hide abstract]
ABSTRACT: The interactions between cancer cells and the extracellular matrix (ECM) regulate cancer progression. The beta1C and beta1A integrins, two cytoplasmic variants of the beta1 integrin subfamily, are differentially expressed in prostate cancer. Using gene expression analysis, we show here that the beta1C variant, an inhibitor of cell proliferation, which is down-regulated in prostate cancer, up-regulates insulin-like growth factor-II (IGF-II) mRNA and protein levels. In contrast, beta1A does not affect IGF-II levels. We provide evidence that beta1C-mediated up-regulation of IGF-II levels increases adhesion to Laminin-1, a basement membrane protein down-regulated in prostate cancer, and that the beta1C cytoplasmic domain contains the structural motif sufficient to increase cell adhesion to Laminin-1. This autocrine mechanism that locally supports cell adhesion to Laminin-1 via IGF-II is selectively regulated by the beta1 cytoplasmic domain via activation of the growth factor receptor binding protein 2-associated binder-1/SH2-containing protein-tyrosine phosphatase 2/phosphatidylinositol 3-kinase pathway. Thus, the concurrent local loss of beta1C integrin, of its ligand Laminin-1, and of IGF-II in the tumor microenvironment may promote prostate cancer cell invasion and metastasis by reducing cancer cell adhesive properties. It is, therefore, conceivable that reexpression of beta1C will be sufficient to revert a neoplastic phenotype to a nonproliferative and highly adherent normal phenotype.Cancer Research 02/2006; 66(1):331-42. · 7.86 Impact Factor -
Article: β1 integrins modulate cell adhesion by regulating insulin-like growth factor-II levels in the microenvironment
Paper. 01/2006; 347. -
Article: Down-regulation of BRCA2 expression by collagen type I promotes prostate cancer cell proliferation.
[show abstract] [hide abstract]
ABSTRACT: BRCA2 is a tumor suppressor gene that when mutated confers an increased susceptibility to developing breast and prostate carcinoma. Besides its role in mediating DNA repair, new evidence suggests that BRCA2 may also play a role in suppressing cancer cell growth. Because altered interactions between neoplastic cells and the surrounding extracellular matrix (ECM) play a pivotal role in unchecked cancer cell proliferation and metastatic progression, we hypothesized that the ECM may have an effect in BRCA2 expression. By using normal and prostate carcinoma cell lines, we demonstrated that although normal cells transiently increase BRCA2 protein levels when adhering to the ECM protein collagen type I (COL1), carcinoma cells exhibit a significant reduction in BRCA2 protein. This aberrant effect is independent from de novo protein synthesis and results from COL1-beta(1) integrin signaling through phosphatidylinositol (PI) 3-kinase leading to BRCA2 ubiquitination and degradation in the proteasome. BRCA2 protein depletion after cancer cell adhesion to COL1 or in small RNA interference assays triggers new DNA synthesis, a trophic effect that is abrogated by recombinant BRCA2 expression. Blocking or inhibiting beta(1) integrin, PI 3-kinase, or proteasome activity all have a negative effect on COL1-mediated DNA synthesis in cancer cells. In normal cells, the transient increase in BRCA2 expression is independent from beta(1) integrin or PI 3-kinase and has no effect in cell proliferation. In summary, these results unravel a novel mechanism whereby prostate carcinoma cell proliferation is enhanced by the down-regulation of BRCA2 expression when interacting with COL1, a major component of the ECM at osseous metastatic sites.Journal of Biological Chemistry 07/2005; 280(23):22482-91. · 4.77 Impact Factor -
Article: Ultrastructural zonal heterogeneity of hepatocytes and mitochondria within the hepatic acinus during liver regeneration after partial hepatectomy.
[show abstract] [hide abstract]
ABSTRACT: Partial hepatectomy (70%) induces cell proliferation until the original mass of the liver is restored. In the first 24 h after partial hepatectomy, drastic changes in the metabolism of the remaining liver have been shown to occur. To evaluate changes in hepatocyte ultrastructure within the hepatic acinus during the liver regenerative process, we investigated, by light and electron microscopy observations on specimens taken 0 h, 24 h and 96 h after partial hepatectomy, the hepatocyte structure and ultrastructure in the periportal and pericentral area of the hepatic acinus, with a particular emphasis on mitochondria ultrastructure. Moreover, some biochemical events that could affect the mitochondria ultrastructure and function were investigated. We found that, 24 h after partial hepatectomy, mitochondria with altered ultrastructure were preferentially localized in the periportal area. Periportal hepatocytes showed also an increase in the number of peroxisomes, free ribosomes, lysosomes and autophagosomes. Altered mitochondria showed swelling, an ultrastructural index of increased membrane permeability, a reduction in the number of cristae, and a rarefied, often vacuoled, matrix. Consistently, an increase in the mitochondrial oxidized/reduced glutathione ratio was found as well as calcium release from mitochondria in a manner inhibited by cyclosporin A. Interestingly, light and electron microscopy analysis showed that the hepatocytes in the periportal area were the cells with the major structural attributes to proliferate. At 96 h after partial hepatectomy, the preferential zonation of altered mitochondria was lost and the normal mitochondrial membrane permeability properties were restored. We suggest that 24 h after partial hepatectomy, a preferential zonation of altered mitochondria in the periportal hepatocytes could be involved in the changes of metabolic and functional heterogeneity of the hepatocytes within the hepatic acinus during the regenerative process.Biology of the Cell 05/2005; 97(4):277-88. · 3.60 Impact Factor -
Article: Transcriptional regulation of beta1 integrin expression in the physio/pathological states of human endometrial tissues.
[show abstract] [hide abstract]
ABSTRACT: beta1C integrin is a spliced variant of the human beta1 integrin family that inhibits cell proliferation, at variance with beta1A that stimulates it. During the transition from normal to neoplastic endometrium, both variants are down-regulated at the mRNA level, but only beta1C at the protein level, suggesting a key role of the regulation of beta1C integrin expression in the pathogenesis of endometrial cancer. In this study we show for the first time that, besides beta1A and beta1C, the beta1B spliced variant is expressed in human endometrium, and is up-regulated in hyperplastic and neoplastic endometria in comparison with normal proliferative endometria. To investigate the mechanisms of regulation of beta1 integrin expression during endometrial cancer progression we compared the transcriptional activity of the beta1 integrin gene in normal and diseased endometria by nuclear run-on analysis and we found it significantly reduced in endometrial adenocarcinoma. On the contrary, hyperplastic endometria showed a 2-fold increase in the beta1 transcription rate that directly correlated with the increase in beta1B, beta1C and beta1A steady-state mRNA levels. Finally, we compared the activity of the distal and proximal promoters of the beta1 gene integrin gene in normal and diseased endometria and we found the activity of the proximal promoter decreased in neoplastic endometria and increased in hyperplastic tissues, whereas the activity of the distal promoter did not change in different endometrial physio/pathological conditions. These findings suggest a complex pattern for regulation of the expression of beta1 integrin variants during endometrial malignant transformation.International Journal of Oncology 03/2005; 26(2):457-65. · 2.40 Impact Factor -
Article: Thyroid hormone treatment of hypothyroid rats restores the regenerative capacity and the mitochondrial membrane permeability properties of the liver after partial hepatectomy.
[show abstract] [hide abstract]
ABSTRACT: We have investigated the effect of thyroid hormone on recovery of liver mass and on the mitochondrial membrane permeability properties during rat liver regeneration after 70% partial hepatectomy (PH). In the euthyroid state, liver weight starts to recover 24 h after PH and is completely restored 96 h after PH. Cyclosporin A (CsA)-sensitive mitochondrial permeability transition (MPT) occurs 24 h after PH, and it has been suggested to act in the signaling mechanism for hepatocyte proliferation. In this study we show that hypothyroidism delays recovery of the liver mass, being only 50% of the initial weight 96 h after PH, and alters the duration and mode of MPT occurrence, first inducing a CsA-insensitive swelling 24 h after PH, followed by a CsA-sensitive swelling 96 h after PH. The occurrence of both CsA-sensitive and -insensitive swelling is shown to be associated with an increase in mitochondrial calcium content. Concurrent with mitochondrial swelling, external release of matrix proteins from mitochondria, such as aspartate aminotransferase and malate dehydrogenase, is shown to be CsA insensitive 24 h after PH and CsA sensitive 96 h after PH. After thyroid hormone administration to hypothyroid rats, the liver regenerative capacity is restored, and the duration and mode of MPT occurrence as well as changes in mitochondrial calcium content become similar to those observed in the euthyroid condition. The results of the present study suggest the involvement of a mitochondria-mediated pathway in regulation of the liver regenerative process by thyroid hormone.Endocrinology 12/2004; 145(11):5121-8. · 4.46 Impact Factor -
Article: Selective modulation of type 1 insulin-like growth factor receptor signaling and functions by beta1 integrins.
[show abstract] [hide abstract]
ABSTRACT: We show here that beta1 integrins selectively modulate insulin-like growth factor type I receptor (IGF-IR) signaling in response to IGF stimulation. The beta1A integrin forms a complex with the IGF-IR and insulin receptor substrate-1 (IRS-1); this complex does not promote IGF-I mediated cell adhesion to laminin (LN), although it does support IGF-mediated cell proliferation. In contrast, beta1C, an integrin cytoplasmic variant, increases cell adhesion to LN in response to IGF-I and its down-regulation by a ribozyme prevents IGF-mediated adhesion to LN. Moreover, beta1C completely prevents IGF-mediated cell proliferation and tumor growth by inhibiting IGF-IR auto-phosphorylation in response to IGF-I stimulation. Evidence is provided that the beta1 cytodomain plays an important role in mediating beta1 integrin association with either IRS-1 or Grb2-associated binder1 (Gab1)/SH2-containing protein-tyrosine phosphate 2 (Shp2), downstream effectors of IGF-IR: specifically, beta1A associates with IRS-1 and beta1C with Gab1/Shp2. This study unravels a novel mechanism mediated by the integrin cytoplasmic domain that differentially regulates cell adhesion to LN and cell proliferation in response to IGF.The Journal of Cell Biology 09/2004; 166(3):407-18. · 10.26 Impact Factor -
Article: Regulation of beta1C and beta1A integrin expression in prostate carcinoma cells.
[show abstract] [hide abstract]
ABSTRACT: beta(1C) and beta(1A) integrins are two splice variants of the human beta(1) integrin subfamily that act as an inhibitor and a stimulator of cell proliferation, respectively. In neoplastic prostate epithelium, both these variants are down-regulated at the mRNA level, but only beta(1C) protein levels are reduced. We used an experimental model consisting of PNT1A, a normal immortalized prostate cell line, and LNCaP and PC-3, two prostate carcinoma cell lines, to investigate both the transcription/post-transcription and translation/post-translation processes of beta(1C) and beta(1A). Transcriptional regulation played the key role for the reduction in beta(1C) and beta(1A) mRNA expression in cancer cells, as beta(1C) and beta(1A) mRNA half-lives were comparable in normal and cancer cells. beta(1C) translation rate decreased in cancer cells in agreement with the decrease in mRNA levels, whereas beta(1A) translation rate increased more than 2-fold, despite the reduction in mRNA levels. Both beta(1C) and beta(1A) proteins were degraded more rapidly in cancer than in normal cells, and pulse-chase experiments showed that intermediates and/or rates of beta(1C) and beta(1A) protein maturation differ in cancer versus normal cells. Inhibition of either calpain- or lysosomal-mediated proteolysis increased both beta(1C) and beta(1A) protein levels, the former in normal but not in cancer cells and the latter in both cell types, albeit at a higher extent in cancer than in normal cells. Interestingly, inhibition of the ubiquitin proteolytic pathway increased expression of ubiquitinated beta(1C) protein without affecting beta(1A) protein levels in cancer cells. These results show that transcriptional, translational, and post-translational processes, the last involving the ubiquitin proteolytic pathway, contribute to the selective loss of beta(1C) integrin, a very efficient inhibitor of cell proliferation, in prostate malignant transformation.Journal of Biological Chemistry 02/2004; 279(3):1692-702. · 4.77 Impact Factor
Top co-authors
Top Journals
Institutions
-
2013
-
NYU Langone Medical Center
New York City, NY, USA
-
-
2004–2013
-
National Research Council - Italy
Roma, Latium, Italy -
Yale-New Haven Hospital
- Department of Pathology
New Haven, CT, USA
-
-
2011
-
University of Texas Southwestern Medical Center
- Department of Pathology
Dallas, TX, USA
-
-
2003–2010
-
National Research Council
- Institute of Biomembrane and Bioenergetics IBBE
Roma, Latium, Italy
-
-
2004–2009
-
University of Massachusetts Medical School
- Department of Cancer Biology
Worcester, MA, USA
-
-
2002–2005
-
Università degli Studi di Bari Aldo Moro
Bari, Apulia, Italy
-
