Suppression of facilitative glucose transporter 1 mRNA can suppress tumor growth

Noguchi, Yoshikazu; Saito, Aya; Miyagi, Yohei; Yamanaka, Shōji; Marat, Doulet; Doi, Chiharu; Yoshikawa, Takaki; Tsuburaya, Akira; Ito, Takaaki; Satoh, Shinobu

doi:10.1016/s0304-3835(00)00392-x

Cited by 68 publications

(59 citation statements)

References 15 publications

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“…Reduced GLUT1 expression following transfection of GLUT1 antisense cDNA into cancer cell lines has been shown to suppress cell growth in vitro and tumor growth in vivo, and to reduce in vitro invasiveness of cells (Noguchi et al, 2000;Ito et al, 2002). Transfection of ras-transformed mouse fibroblasts with a GLUT1 antisense vector resulted in decreased glucose uptake and reduced ability to form colonies in soft agar compared to non-transfected cells (Choi et al, 1995).…”

Section: Implications and Conclusionmentioning

confidence: 99%

“…Human leukemia cells transfected with antisense GLUT1 had reduced GLUT1 mRNA levels and cell proliferation (Chan et al, 1999). Noguchi et al (2000) transfected a gastric cancer cell line with antisense GLUT1. These cells had significantly reduced glucose uptake and GLUT1 mRNA levels, and significantly fewer cells in S phase compared to vector control cells.…”

Section: Implications and Conclusionmentioning

confidence: 99%

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Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer

Macheda

Rogers

Best

2004

Journal Cellular Physiology

1,034

888

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Malignant cells are known to have accelerated metabolism, high glucose requirements, and increased glucose uptake. Transport of glucose across the plasma membrane of mammalian cells is the first rate-limiting step for glucose metabolism and is mediated by facilitative glucose transporter (GLUT) proteins. Increased glucose transport in malignant cells has been associated with increased and deregulated expression of glucose transporter proteins, with overexpression of GLUT1 and/or GLUT3 a characteristic feature. Oncogenic transformation of cultured mammalian cells causes a rapid increase of glucose transport and GLUT1 expression via interaction with GLUT1 promoter enhancer elements. In human studies, high levels of GLUT1 expression in tumors have been associated with poor survival. Studies indicate that glucose transport in breast cancer is not fully explained by GLUT1 or GLUT3 expression, suggesting involvement of another glucose transporter. Recently, a novel glucose transporter protein, GLUT12, has been found in breast and prostate cancers. In human breast and prostate tumors and cultured cells, GLUT12 is located intracellularly and at the cell surface. Trafficking of GLUT12 to the plasma membrane could therefore contribute to glucose uptake. Several factors have been implicated in the regulation of glucose transporter expression in breast cancer. Hypoxia can increase GLUT1 levels and glucose uptake. Estradiol and epidermal growth factor, both of which can play a role in breast cancer cell growth, increase glucose consumption. Estradiol and epidermal growth factor also increase GLUT12 protein levels in cultured breast cancer cells. Targeting GLUT12 could provide novel methods for detection and treatment of breast and prostate cancer.

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Section: Implications and Conclusionmentioning

confidence: 99%

Section: Implications and Conclusionmentioning

confidence: 99%

Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer

Macheda

Rogers

Best

2004

Journal Cellular Physiology

1,034

888

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“…4 GLUT1 is ubiquitously expressed and its overexpression has been studied in primary tumors of many tissues including lung, 6,7 breast, 8,9 colon, 10,11 and stomach. 12,13 Even though most studies show an increase in Class I (GLUT1-4) glucose transport facilitators in tumor tissues, some studies suggest that these transporters are not significantly increased in some primary tumors. 14 Increased expression of the newly discovered Class III glucose transporters (GLUT6, À8, À10, and À12) might account for the increase in substrate for the observed augmented glycolytic activity of these tumors.…”

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confidence: 99%

GLUT1 and GLUT8 in endometrium and endometrial adenocarcinoma

et al. 2006

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Glucose is provided to cells by a family of glucose transport facilitators known as GLUTs. These transporters are expressed in a tissue specific manner and are overexpressed in many primary tumors of these tissues. Regulation of glucose transport facilitator expression has been demonstrated in endometrial tissue and endometrial adenocarcinoma. The following experiments were conducted to quantify and localize the expression of GLUT1 and GLUT8 in benign endometrium and compare this expression to endometrial cancer. Endometrial tissue samples were obtained from random hysterectomy specimens of patients with benign indications for surgery and endometrial cancer. Immunoblot and immunolocatization studies were performed using GLUT1 and GLUT8 specific antisera. Endometrial samples from 65 women who had undergone hysterectomy were examined (n ¼ 38 benign, n ¼ 27 malignant). A 44 and a 35.4 kDa immunoreacive species was demonstrated in endometrium and endometrial cancer for GLUT1 and GLUT8, respectively. Upregulation of GLUT1 expression was demonstrated with increasing grade of tumors (Po0.002). GLUT8 expression was increased in all tumor subtypes compared to atrophic endometrium (Po0.001). Apical localization by GLUT1 and GLUT8 was demonstrated in endometrial glands. GLUT1 and GLUT8 demonstrated diffuse intracellular localization in the cancer subtypes. GLUT1 and GLUT8 are expressed in both human endometrium and endometrial cancer. There appears to be a step-wise progression in GLUT1 and GLUT8 expression as tumor histopathology worsens. GLUT1 and GLUT8 may be important markers in tumor differentiation, as well as providing energy to rapidly dividing tumor cells.

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“…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. 30 Suppression of glucose transporter 1 (GLUT1) in the human gastric cancer cell line MKN45 resulted in a decreased number of cells in S-phase, at least partially due to an increase in p21 expression.…”

Section: Discussionmentioning

confidence: 99%

“…30 Suppression of glucose transporter 1 (GLUT1) in the human gastric cancer cell line MKN45 resulted in a decreased number of cells in S-phase, at least partially due to an increase in p21 expression. 31 It remains to be determined whether modulation of other CD98-related functions such as mitogen stimulation or integrin activation are affected in cells with altered expression of LAT1. In vivo studies now in progress will mitigate the complication of induction of LAT1 expression in response to in vitro cell culture conditions and further assess the effects of this molecule on tumor growth and hepatic functions under more physiological conditions.…”

Section: Discussionmentioning

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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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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Suppression of facilitative glucose transporter 1 mRNA can suppress tumor growth

Cited by 68 publications

References 15 publications

Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer

Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer

GLUT1 and GLUT8 in endometrium and endometrial adenocarcinoma

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

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