Amino acid transport system L is a cell membrane protein that transports neutral amino acid and known to be the major route of neutral amino acids for cell proliferation.1-3) Kanai et al. identified the first isoform of amino acid transport system L (L-type amino acid transporter 1, LAT1) from C6 glioma cells.4) It is predicted to be 12-membrane-spanning proteins, and mediates Na ϩ -independent amino acid exchange and prefers large neutral amino acids with bulky or branched side chains for its substrates. [4][5][6][7][8] Following the molecular identification of LAT1, the second isoform of amino acid transport system L (L-type amino acid transporter 2, LAT2) has been identified. [9][10][11] It has the characteristics of transporting small neutral amino acids as well as large neutral amino acids. [10][11][12] LAT1 is only expressed in restricted organs such as brain, spleen, placenta and testis. 4,13) However, LAT2 is more ubiquitously expressed than LAT1. [10][11][12] Importantly, LAT1 is highly expressed in malignant tumors presumably to support their continuous growth and proliferation. 4,5,14,15) Based on the characteristics of LAT1 and LAT2, it is proposed that the manipulation of system L activity, particularly that of LAT1, would have therapeutic implications for cancer treatment. If the activity of LAT1 should be suppressed and thereby the depletion of intracellular neutral amino acids should be induced, this would be helpful for inducing the inhibition of cancer cell growth. However, the mechanism by which inhibition of LAT1 can cause cancer cell growth suppression or cytotoxicity of cancer cells is not entirely clear.2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) is a model compound for the study of amino acid transporters, as it is a system L selective inhibitor. [4][5][6]11,16,17) Substrates for amino acid transport system L include several essential amino acids such as leucine, isoleucine, valine, phenylalanine, methionine and histidine.1-3) Therefore, the suppression of L-type amino transpoter activity using BCH could be effective in the retardation of tumor cell growth by depleting the intracellular essential amino acids. In this study, we attempted to clarify the effect of BCH on the expression of factors regulating the cell cycle to cause cell cycle arrest in KB human oral cancer cells. We report here that the BCH arrests KB cell growth at G1 phase of cell cycle through the inhibition of cyclin D3-cyclin-dependent protein kinase 6 (CDK6) complex expression while increasing the expression of p27, a CDK inhibitor. Cell Cultures KB cells were grown in Dulbecco's modi- The purpose of this study was to examine the effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), an inhibitor of L-type amino acid transporters, on the cell growth suppression in KB human oral cancer cells and to study the roles of cell cycle regulatory factors in the BCH-induced growth inhibition. The effect of BCH on cell growth suppression and the influence of BCH to cell cycle regulatory factors in KB cell gro...
Cancer relapse is the most common cause of mortality in breast cancer patients. The cancer stem cell (CSC) hypothesis proposes that CSCs are the root of cancer. CSC-targeted therapies may prevent cancer relapse and provide more effective treatment. It has been known that stem cells can be enriched in non-adherent sphere culture. To identify molecular targets in breast CSC, we compared transcription levels of stem cell-related genes between tumorspheres established from Balb/c mice-derived 4T1 mammary carcinoma and mammospheres from the mammary glands of Balb/c mice. The most differentially expressed gene was found to be Wingless-type MMTV integration site family, member 1 (WNT1). To determine whether WNT1 has any relevance in breast carcinoma, we analyzed the expression of WNT1 in the human matched normal breast and breast cancer samples. Immunofluorescent staining showed that WNT1 expression was elevated ∼17-63-fold in cancerous tissues compared with non-cancerous tissues from the same breast cancer patients. Functionally, knockdown of WNT1 in 4T1 cells reduced the Aldefluorpos cell compartment enriched in CSCs and suppressed the properties of CSCs, including anti-apoptosis, sphere-forming ability, and tumor initiation ability in vivo. Collectively, these results show that WNT1 expression gives rise to properties of CSC in breast cancer. Therefore, the targeting of WNT1-associated signaling may provide an effective therapeutic approach in the treatment of advanced breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5201. doi:1538-7445.AM2012-5201
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