Controlling Tumor-Derived and Vascular Endothelial Cell Growth

Papetti, Michael; Herman, Ira M.

doi:10.1016/s0002-9440(10)61683-5

Cited by 11 publications

(11 citation statements)

References 65 publications

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“…How this decrease in cell number may occur independent of an effect on amino acid transport is not known. Such growth related effects are similar to previous research in which 4F2 expression or function has been blocked, 21 as well as to studies blocking primary transporters for glutamine 30 and glucose. 31 Stable transfection of the human hepatoma cell line SK-Hep1 with an antisense RNA expression plasmid for the glutamine transporter ATB0/ASCT2 decreased mRNA levels 73% and resulted in decreased cell number at 48 hr.…”

Section: Discussionsupporting

confidence: 86%

“…It has been shown previously that 4F2 overexpression in NIH 3T3 cells results in changes consistent with malignant transformation 17,20 and monoclonal antibodies against 4F2 have been shown to inhibit tumor cell nucleic acid synthesis and proliferation of several cell types. 21,22 The malignant alterations, however, required association with the CD98 complex light chain. 20 We utilized a tetracycline-inducible adenoviral expression system (TET-Off) to alter levels of LAT1, with the goal of assessing the short-term functional impact on in vitro phenotypes important to cell growth and survival.…”

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confidence: 99%

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Adenoviral modulation of the tumor‐associated system L amino acid transporter, LAT1, alters amino acid transport, cell growth and 4F2/CD98 expressionwith cell‐type specific effects in cultured hepatic cells

Storey

Fugère

Lesieur-Brooks

et al. 2005

Intl Journal of Cancer

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Altered expression of metabolite transporters is observed frequently in tumor cell lines and primary neoplasms. The extent to which these may to contribute to the growth autonomy associated with cancer is not clear. LAT1 is a major L-type amino acid transporter over-expressed in a variety of cancer types and a light chain component of the CD98 heterodimer. We utilized an adenoviral expression system to modulate the level of LAT1 in a hepatic in vitro model to examine phenotypic changes associated with short-term exogenous and blocked expression. LAT1 levels were increased three fold and resulted in increased L-type amino acid transport as a result of adenoviral expression in murine hepatocytes. The protein was expressed on the cell surface and complexed with the CD98 heavy chain known as 4F2. Surprisingly, levels of the total CD98 protein complex were increased 2.4-fold as a result of adenoviral expression of light chain only, suggesting coordinate regulation. Exogenous overexpression was less effective in normal rat liver cells relative to mouse. LAT1 antisense expression in hepatic tumor cells resulted in a modest though statistically significant decrease in cell number, viability and S-phase cells over a 5-day period relative to controls despite the absence of a significant decrease in L-type transport over this period. These studies are preparatory to in vivo efforts focusing on LAT1/CD98 as a potential therapeutic target. ' 2005 Wiley-Liss, Inc.Key words: LAT1; 4F2; CD98; leucine; adenovirus Recent studies have demonstrated that LAT1 is a major L-type amino acid transporter in a variety of cancer cells including hepatic, 1-3 oral, 4 breast, 5 bladder 6 and colon. 7 This predicted 12 transmembrane spanning protein mediates sodium independent transport of large neutral amino acids including several essential amino acids and is a major route for providing tumor cells with branched and aromatic amino acids. Because these amino acids are indispensable for growth and proliferation-dependent protein synthesis, LAT1 represents a target of high potential therapeutic interest. LAT1 exhibits broad substrate selectivity and is responsible for transport not only of naturally occurring amino acids, but also amino acid-related drugs such as l-dopa, melphalan, (an anti-cancer phenylalanine mustard), triiodothyronine and thyroxine and gabapentin, an anti-convulsant. Functional expression of LAT1 in the plasma membrane requires an additional single transmembrane glycoprotein known as 4F2 antigen or heavy chain and together these form a heterodimeric complex known as CD98. [8][9][10][11][12][13] The glycoprotein-associated transporters are a novel class of amino acid transporters recently the subject of much interest not only in relation to transport but also to CD98-linked functions in cell activation, integrin signaling, cell fusion and malignant transformation. [14][15][16][17] Our research has utilized a tetracycline-inducible adenoviral expression system (TET-Off) system to alter levels of LAT1 and 4F2 in vitro. We have...

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Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 99%

Adenoviral modulation of the tumor‐associated system L amino acid transporter, LAT1, alters amino acid transport, cell growth and 4F2/CD98 expressionwith cell‐type specific effects in cultured hepatic cells

Storey

Fugère

Lesieur-Brooks

et al. 2005

Intl Journal of Cancer

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“…31 Although biologically active small molecules against CD98-associated light chains have been identified, anti-CD98 antibodies provide another approach to modifying amino acid transport. 5,[11][12][13] Our data demonstrate for the first time that CD98 is overexpressed in CD34 1 -primary AML cells and in the squamous cell carcinoma subtype of NSCLC (Supporting Information Figs. S1a and S1b).…”

Section: Discussionmentioning

confidence: 90%

“…5,[8][9][10] Murine monoclonal antibodies to CD98 inhibit lymphocyte proliferation and the growth of bladder cancer, lymphoma, glioma, prostate and colon cancer cells in preclinical models. [11][12][13] To identify therapeutic anti-CD98 antibodies with significant antitumor activity, we used in vivo phenotypic screening. The advantage of phenotypic screening for antibodies against novel targets compared with the more common target-based screening, is 2-fold.…”

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confidence: 99%

Antitumor activity of an anti‐CD98 antibody

et al. 2015

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CD98 is expressed on several tissue types and specifically upregulated on fast-cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98-specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell-line derived xenograft models and was as efficacious as standard of care carboplatin in patient-derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase-3 and -7-mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors.CD98 is a heterodimeric protein that comprises a heavy and light chain. The CD98 heavy chain is a type II transmembrane glycoprotein that forms a heterodimer via covalent linkage to one of 6 amino acid transporters. 1,2 CD98 is overexpressed on the cell surface of almost all tumor cells, regardless of tissue origin and increased expression of a CD98-light chain, L-type amino acid transporter 1 (LAT-1) occurs in many types of human cancers, including breast, colon, oral, ovarian, esophageal, glioma and leukemia. 3,4 Increased uptake of amino acids supports the high growth rate of cancer cells by providing the building blocks for protein synthesis. [4][5][6] Moreover, the higher expression of CD98 heavy chain and LAT-1 in metastatic vs. primary tumors suggests that over-expression of CD98/LAT-1 may facilitate progression and metastasis of human cancers.CD98 also regulates integrin signaling by association with integrin b-subunits, thereby controlling cell proliferation, survival, migration, epithelial adhesion and polarity. 3,7 The function of CD98 in regulating both amino acid transport and integrin signaling can contribute to the rapid proliferation and clonal expansion of lymphocytes and tumor cells. 3 The expression pattern and pleiotropic function of CD98 heavy and light chains suggest these proteins are promising targets for treatment of a variety of human cancers. Although small molecule inhibitors of LAT-1 activity have demonstrated preclinical antitumor activity in a number of cancer cell types, including NSCLC, colon cancer, oral cancer and breast cancer, development of antibodies against CD98 heavy chain has received less focus. 5,[8][9][10] Murine monoclonal antibodies to CD98 inhibit lymphocyte proliferation and the growth of bladder cancer, lymphoma, glioma, prostate and colon cancer cells in preclinical models. [11][12][13] To identify therapeutic anti-CD98 antibodies with significant antitumor activity, we ...

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“…In vitro binding studies have shown that the 4F2 heavy chain (CD98) interacts specifically with integrin ␤1A (18), and it has been implicated in cell activation and proliferation in various cancer cells, including those of colon, breast, and lung (19). Moreover, there is a recent report demonstrating that a specific antibody targeting the 4F2 heavy chain antigen inhibited the growth of tumor cells that expressed the antigen (20) . FIG.…”

Section: Figmentioning

confidence: 99%

Global Profiling of the Cell Surface Proteome of Cancer Cells Uncovers an Abundance of Proteins with Chaperone Function

Shin¹,

Wang²,

Yim³

et al. 2003

Journal of Biological Chemistry

496

377

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There is currently limited data available pertaining to the global characterization of the cell surface proteome. We have implemented a strategy for the comprehensive profiling and identification of surface membrane proteins. This strategy has been applied to cancer cells, including the SH-SY5Y neuroblastoma, the A549 lung adenocarcinoma, the LoVo colon adenocarcinoma, and the Sup-B15 acute lymphoblastic leukemia (B cell) cell lines and ovarian tumor cells. Surface membrane proteins of viable, intact cells were subjected to biotinylation then affinity-captured and purified on monomeric avidin columns. The biotinylated proteins were eluted from the monomeric avidin columns as intact proteins and were subsequently separated by two-dimensional PAGE, transferred to polyvinylidene difluoride membranes, and visualized by hybridization with streptavidin-horseradish peroxidase. Highly reproducible, but distinct, two-dimensional patterns consisting of several hundred biotinylated proteins were obtained for the different cell populations analyzed. Identification of a subset of biotinylated proteins among the different cell populations analyzed using matrix-assisted laser desorption ionization and tandem mass spectrometry uncovered proteins with a restricted expression pattern in some cell line(s), such as CD87 and the activin receptor type IIB. We also identified more widely expressed proteins, such as CD98, and a sushi repeat-containing protein, a member of the selectin family. Remarkably, a set of proteins identified as chaperone proteins were found to be highly abundant on the cell surface, including GRP78, GRP75, HSP70, HSP60, HSP54, HSP27, and protein disulfide isomerase. Comprehensive profiling of the cell surface proteome provides an effective approach for the identification of commonly occurring proteins as well as proteins with restricted expression patterns in this compartment.

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Controlling Tumor-Derived and Vascular Endothelial Cell Growth

Cited by 11 publications

References 65 publications

Adenoviral modulation of the tumor‐associated system L amino acid transporter, LAT1, alters amino acid transport, cell growth and 4F2/CD98 expressionwith cell‐type specific effects in cultured hepatic cells

Adenoviral modulation of the tumor‐associated system L amino acid transporter, LAT1, alters amino acid transport, cell growth and 4F2/CD98 expressionwith cell‐type specific effects in cultured hepatic cells

Antitumor activity of an anti‐CD98 antibody

Global Profiling of the Cell Surface Proteome of Cancer Cells Uncovers an Abundance of Proteins with Chaperone Function

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