scholarly journals Polyamine transport is mediated by both endocytic and solute carrier transport mechanisms in the gastrointestinal tract

2010 ◽  
Vol 299 (2) ◽  
pp. G517-G522 ◽  
Author(s):  
Takeshi Uemura ◽  
David E. Stringer ◽  
Karen A. Blohm-Mangone ◽  
Eugene W. Gerner
Keyword(s):  
Carrier Transport ◽  
Cellular Functions ◽  
Synthesis Inhibitor ◽  
Polyamine Synthesis ◽  
Caveolin 1 ◽  
Polyamine Transport ◽  
Solute Carrier ◽  
Polyamine Uptake ◽  
Solute Carrier Transporter ◽  
Oxide Synthase

The polyamines spermidine and spermine, and their precursor putrescine, are required for cell growth and cellular functions. The high levels of tissue polyamines are implicated in carcinogenesis. The major sources of exogenous polyamines are diet and intestinal luminal bacteria in gastrointestinal (GI) tissues. Both endocytic and solute carrier-dependent mechanisms have been described for polyamine uptake. Knocking down of caveolin-1 protein increased polyamine uptake in colon cancer-derived HCT116 cells. Dietary supplied putrescine was accumulated in GI tissues and liver in caveolin-1 knockout mice more than wild-type mice. Knocking out of nitric oxide synthase (NOS2), which has been implicated in the release of exogenous polyamines from internalized vesicles, abolished the accumulation of dietary putrescine in GI tissues. Under conditions of reduced endogenous tissue putrescine contents, caused by treatment with the polyamine synthesis inhibitor difluoromethylornithine (DFMO), small intestinal and colonic mucosal polyamine contents increased with dietary putrescine levels, even in mice lacking NOS2. Knocking down the solute carrier transporter SLC3A2 in HCT116-derived Hkh2 cells reduced the accumulation of exogenous putrescine and total polyamine contents in DFMO treated cells, relative to non-DFMO-treated cells. These data demonstrate that exogenous putrescine is transported into GI tissues by caveolin-1- and NOS2-dependent mechanisms, but that the solute carrier transporter SLC3A2 can function bidirectionally to import putrescine under conditions of low tissue polyamines.

Unusual aspects of the polyamine transport system affect the design of strategies for use of polyamine analogues in chemotherapy

2007 ◽  
Vol 35 (2) ◽  
pp. 318-321 ◽  
Author(s):  
J.L.A. Mitchell ◽  
T.K. Thane ◽  
J.M. Sequeira ◽  
R. Thokala
Keyword(s):  
Regulatory Protein ◽  
Feedback System ◽  
Uptake System ◽  
Polyamine Synthesis ◽  
Polyamine Analogues ◽  
Binding Partners ◽  
Polyamine Transport ◽  
Polyamine Uptake ◽  
Tumour Cell Growth

One strategy for inhibiting tumour cell growth is the use of polyamine mimetics to depress endogenous polyamine levels and, ideally, obstruct critical polyamine-requiring reactions. Such polyamine analogues make very unusual drugs, in that extremely high intracellular concentrations are required for growth inhibition or cytotoxicity. Cells exposed to even sub-micromolar concentrations of such analogues can achieve effective intracellular levels because these compounds are incorporated by the very aggressive polyamine uptake system. Once incorporated to these levels, many of these analogues induce the synthesis of a regulatory protein, antizyme, which inhibits both polyamine synthesis and the transporter they used to enter the cell. Thus this feedback system allows steady-state maintenance of effective cellular doses of such analogues. Accordingly, effective cellular levels of polyamine analogues are generally inversely related to their capacity to induce antizyme. Antizyme activity is down-regulated by interaction with several binding partners, most notably antizyme inhibitor, and at least a few tumour tissues exhibit deficiencies in antizyme expression. Our studies explore the role of antizyme induction by several polyamine analogues in their physiological response and the possibility that cell-to-cell differences in antizyme expression may contribute to variable sensitivities to these agents.

scholarly journals Transport of polyamines in Drosophila S2 cells: kinetics, pharmacology and dependence on the plasma membrane proton gradient

2005 ◽  
Vol 393 (2) ◽  
pp. 583-589 ◽  
Author(s):  
Rafael Romero-Calderón ◽  
David E. Krantz
Keyword(s):  
Mammalian Cells ◽  
Organic Anion ◽  
S2 Cells ◽  
Transport Activity ◽  
Molecular Identity ◽  
Polyamine Transport ◽  
Drosophila S2 Cells ◽  
Solute Carrier ◽  
Polyamine Uptake

Polyamine transport activities have been described in diverse multicellular systems, but their bioenergetic mechanisms and molecular identity remain unclear. In the present paper, we describe a high-affinity spermine/spermidine transport activity expressed in Drosophila S2 cells. Ion-replacement experiments indicate that polyamine uptake across the cell membrane is Na+-, K+-, Cl−- and Ca2+-independent, but pH-sensitive. Additional experiments using ionophores suggest that polyamine uptake may be H+-coupled. Pharmacological experiments show that polyamine uptake in S2 cells is selectively blocked by MGBG {methylglyoxal bis(guanylhydrazone) or 1,1′-[(methylethanediylidine)-dinitrilo]diguanidine} and paraquat (N,N-dimethyl-4,4′-bipyridylium), two known inhibitors of polyamine uptake in mammalian cells. In addition, inhibitors known to block the Slc22 (solute carrier 22) family of organic anion/cation transporters inhibit spermine uptake in S2 cells. These data and the genetic tools available in Drosophila will facilitate the molecular identification and further characterization of this activity.

scholarly journals Caveolins; An Assailant or An Ally of Various Cellular Disorders

Drug Research ◽  
2019 ◽  
Vol 69 (08) ◽  
pp. 419-427 ◽  
Author(s):  
Ritesh Kumar Srivastav ◽  
Tarique Mahmood Ansari ◽  
Mahesh Prasad ◽  
Vishal Kumar Vishwakarma ◽  
Paramdeep Bagga ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mammalian Cells ◽  
Dominant Role ◽  
Cholesterol Transport ◽  
Cellular Functions ◽  
Caveolin 1 ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Signal Regulation ◽  
Cardioprotective Action

AbstractCaveolae have impressive morphological highlights of the cytomembrane of mammalian cells which involve in wide diversity of cellular functions involving signaling pathways and cholesterol hastening. Caveolin proteins possess a ‘scaffolding’ domain which for caveolin-1 and caveolin-3 appear to act a dominant role in signal regulation through caveolae. Caveolin-1 is treated to be protein in the cytomembrane entrapped with caveolae in endothelial cells and vascular smooth muscle cells which diminish nitric oxide (NO) by fill up the calcium/calmodulin (Ca2+/CaM) confining point of endothelial nitric oxide synthase (eNOS), decrease NO generation produce endothelial dysfunction and atherosclerotic injury development. It is a cholesterol-binding layer protein associated with cell cholesterol transport and also shows cardioprotective action through ischemic preconditioning (IPC) in diabetic and postmenopausal rat heart. Additionally it is ensnared in the procedures of tumorigenesis, prostate disease, and inflammation. The present study in the paper is to explore the structural functionalities of caveolins and their contributory role in CVS disorders and various other diseases.

Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma

2019 ◽  
Vol 11 (477) ◽  
pp. eaau1099 ◽  
Author(s):  
Laura D. Gamble ◽  
Stefania Purgato ◽  
Jayne Murray ◽  
Lin Xiao ◽  
Denise M. T. Yu ◽  
...  
Keyword(s):  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Tumor Development ◽  
Compensatory Mechanisms ◽  
Polyamine Synthesis ◽  
Solute Carrier ◽  
Polyamine Uptake ◽  
Rate Limiting ◽  
Extended Survival ◽  
Transcriptional Target

Amplification of the MYCN oncogene is associated with an aggressive phenotype and poor outcome in childhood neuroblastoma. Polyamines are highly regulated essential cations that are frequently elevated in cancer cells, and the rate-limiting enzyme in polyamine synthesis, ornithine decarboxylase 1 (ODC1), is a direct transcriptional target of MYCN. Treatment of neuroblastoma cells with the ODC1 inhibitor difluoromethylornithine (DFMO), although a promising therapeutic strategy, is only partially effective at impeding neuroblastoma cell growth due to activation of compensatory mechanisms resulting in increased polyamine uptake from the surrounding microenvironment. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as the key transporter involved in polyamine uptake in neuroblastoma. Knockdown of SLC3A2 in neuroblastoma cells reduced the uptake of the radiolabeled polyamine spermidine, and DFMO treatment increased SLC3A2 protein. In addition, MYCN directly increased polyamine synthesis and promoted neuroblastoma cell proliferation by regulating SLC3A2 and other regulatory components of the polyamine pathway. Inhibiting polyamine uptake with the small-molecule drug AMXT 1501, in combination with DFMO, prevented or delayed tumor development in neuroblastoma-prone mice and extended survival in rodent models of established tumors. Our findings suggest that combining AMXT 1501 and DFMO with standard chemotherapy might be an effective strategy for treating neuroblastoma.

Prevention of Metastasis by a Polyamine Synthesis Inhibitor in an Animal Bone Metastasis Model

Oncology ◽  
2000 ◽  
Vol 59 (1) ◽  
pp. 75-80 ◽  
Author(s):  
Hiroki Wakabayashi ◽  
Hiroshige Hibasami ◽  
Kohji Iida ◽  
Norifumi Satoh ◽  
Takashi Yamazaki ◽  
...  
Keyword(s):  
Bone Metastasis ◽  
Synthesis Inhibitor ◽  
Polyamine Synthesis ◽  
Animal Bone ◽  
Metastasis Model

The Candida albicans plasma membrane protein Rch1p, a member of the vertebrate SLC10 carrier family, is a novel regulator of cytosolic Ca2+ homoeostasis

2012 ◽  
Vol 444 (3) ◽  
pp. 497-502 ◽  
Author(s):  
Linghuo Jiang ◽  
Joerg Alber ◽  
Jihong Wang ◽  
Wei Du ◽  
Xuexue Yang ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Candida Albicans ◽  
Plasma Membrane ◽  
Membrane Protein ◽  
Solute Carrier Family ◽  
Plasma Membrane Protein ◽  
Cellular Functions ◽  
Downstream Target ◽  
Solute Carrier ◽  
High Concentrations

Candida albicans RCH1 (regulator of Ca2+ homoeostasis 1) encodes a protein of ten TM (transmembrane) domains, homologous with human SLC10A7 (solute carrier family 10 member 7), and Rch1p localizes in the plasma membrane. Deletion of RCH1 confers hypersensitivity to high concentrations of extracellular Ca2+ and tolerance to azoles and Li+, which phenocopies the deletion of CaPMC1 (C. albicans PMC1) encoding the vacuolar Ca2+ pump. Additive to CaPMC1 mutation, lack of RCH1 alone shows an increase in Ca2+ sensitivity, Ca2+ uptake and cytosolic Ca2+ level. The Ca2+ hypersensitivity is abolished by cyclosporin A and magnesium. In addition, deletion of RCH1 elevates the expression of CaUTR2 (C. albicans UTR2), a downstream target of the Ca2+/calcineurin signalling. Mutational and functional analysis indicates that the Rch1p TM8 domain, but not the TM9 and TM10 domains, are required for its protein stability, cellular functions and subcellular localization. Therefore Rch1p is a novel regulator of cytosolic Ca2+ homoeostasis, which expands the functional spectrum of the vertebrate SLC10 family.

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